Therapeutic compounds

ABSTRACT

The invention provides compounds of formula Ia′, Ib′, Ic′, and Id′: 
     
       
         
         
             
             
         
       
     
     and pharmaceutically acceptable salts thereof, wherein the variables A, R 6 , R 7 , R 8 , R 9 , R x , L, X, Y, and Z have the meaning as described herein. The compounds are useful for reducing endoplasmic reticulum stress and for producing analgesia in an animal.

PRIORITY

This Application claims priority to 44U.S. Provisional Patent Application No. 62/446087, filed 13 Jan. 2017. The entire content of U.S. Provisional Patent Application No. 62/446,087 is hereby incorporated herein by reference.

BACKGROUND

Parkinson's Disease (PD) is a common, late onset, progressive neurodegenerative disease characterized by the selective loss of various neuronal populations, including the dopaminergic (DAergic) neurons of substantia nigra, pars compacta (SNpc), and the presence of fibrillar, cytoplasmic inclusions called Lewy bodies (LBs) and Lewy neurites (LNs). While degeneration of the SNpc DAergic neurons is responsible for much of the motoric abnormalities, neurodegeneration in PD extends well beyond the SNpc DAergic neurons (Del Tredici K, et al., (2002) J Neuropathol Exp Neurol 61(5):413-426; and Braak H, et al. (2003) Neurobiol Aging 24(2):197-211). The extranigral symptoms of PD are often more debilitating for patients. While the causes of disease is unknown in most cases of PD, the current view is that abnormalities in a neuronal protein called α-synuclein (αS) is responsible for the progressive nature of PD as well as extranigral degeneration. Given this view, compounds that can ameliorate αS abnormalities and/or associated neurodegeneration would qualify as disease modifying therapies for sporadic PD cases. Unfortunately, there are no therapies that can alter the progressive nature of PD.

The endoplasmic reticulum stress/unfolded protein response (ERS/UPR) is an integrated cellular response to the accumulation of misfolded proteins, particularly resulting from ER dysfunction, in attempts to protect cells from accumulation of toxic misfolded proteins (Ron D & Walter P (2007) Nat Rev Mol Cell Biol 8(7):519-529; and Kim I, et al. (2008) Nat Rev Drug Discov 7(12):1013-1030). However, chronic unabated ERS leads to the activation cell death cascade. Potential involvement of chronic ERS in αS-dependent neurodegeneration was first demonstrated in a PC12 cell model of αS toxicity (Smith W W, et al. (2005) Hum Mol Genet 14(24):3801-3811). A recent series of reports suggest that increased αS expression can cause ER stress in yeast and other cells by interrupting Rab-dependent ER to Golgi membrane trafficking (Cooper AA, et al. (2006) Science 313(5785):324-328). It is shown that progressive ERS and activation of ER associated cell death pathway occurs with the accumulation of αS oligomers in the ER (Colla E, et al. (2012) J Neurosci 32(10):3306-3320; and Colla E, et al. (2012) J Neurosci 32(10):3301-3305). Moreover, the pathologic relevance of ERS in disease by showing that pharmacological attenuation of ERS can delay disease onset (Colla E, et al. (2012) J Neurosci 32(10):3306-3320).

Chronic ERS is important pathologic factor in α-synucleinopathy. The toxic nature of the ER associated αS oligomers are also supported by the fact that the accumulation of αS in the ER is associated with the onset of α-synucleinopathy and activation of ER-stress response/unfolded-protein response (UPR) as indicated by increase in ER chaperones in neurons exhibiting αS pathology onset (Colla E, et al. (2012) J Neurosci 32(10):3306-3320). It is suggested that ERS is a valid target for development of disease modifying therapy for PD. However, while endoplasmic reticulm stress/unfolded protein response (ERS/UPR) has been implicated in the disease mechanism for many neurodegenerative diseases, there has not been a clinical compound that has targeted this pathway.

Currently, there is a need for new methods to treat PD and other neurodegenerative diseases.

In addition, there are three α2-adrenergic receptor subtypes, α_(2A), α_(2B) and α_(2C). All there subtypes are involved in the control of pain perception in mice. The antihypertensive (sedative) effect in mice is solely mediated by the α_(2A)-receptor subtype. Compounds that show selective affinities towards 2B and/or 2C would remain of the analgesic activity without the undesirable antihypertensive or other side effects. These compounds would not possess the dependency issues as most of the analgesics in the market do. There is currently also a need for new compounds with selective α_(2A)-receptor subtype selectivity. In addition, there is need for new methods to produce analgesia.

SUMMARY

The invention provides a method for treating neurodegenerative disorders in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′:

or a pharmaceutically acceptable salt thereof;

i) wherein the compound of formula Ia′:

ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN;

L is selected from the group consisting of:

—CH₂CH₂—, —CH₂NH—, —CH₂C(═O)—, —CH(OH)CH₂—,

R^(L) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₈ cycloalkyl;

ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(y), —SR^(y), —N(R^(y))₂, —NO₂ or —CN;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(f))₂, oxo, —NO₂ or —CN; or R⁶ and R⁸ taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

R⁸ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN; or R⁶ and R⁸ taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

X is ═O, ═S or ═N—R^(x); wherein R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(y) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(y) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

ii) wherein the compound of formula Ib′:

ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN;

Y is S or —NR⁶—;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(a))₂, oxo, —NO₂ or —CN;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

R⁸ is hydrogen, phenyl, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —N(R^(h))₂, oxo, —NO₂ or—CN;

Rx is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

iii) wherein the compound of formula Ic′:

ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN;

L is —CH═N—, or C₁₋₄ alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C₃₋₈ cycloalkyl;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

ring Z is heteroaryl or unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from oxo (═O), C₁₋₄ alkyl, —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

iv) wherein the compound of formula Id′:

ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN; and

R⁹ is hydrogen or —C(═NH)—NH₂.

The invention also provides a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof;

provided that the compound is not:

The invention also provides a pharmaceutical composition comprising a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides a method for producing analgesia in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′ or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising: 1) a drug that is associated with unwanted endoplasmic reticulum stress, 2) a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof, and 3) a pharmaceutically acceptable carrier;

provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not

or a pharmaceutically acceptable salt thereof.

The invention also provides a method for reducing endoplasmic reticulum stress in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof;

provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not

or a pharmaceutically acceptable salt thereof.

The invention also provides a method for reducing drug-induced toxicity in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof.

The invention also provides a method for treating a disease selected from the group consisting of diabetes, viral infection, and cancer in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof;

provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not

or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of formula Ia′, Ib′, Ic′, or Id′ or a pharmaceutically acceptable salt thereof.

The invention also provides a pharmaceutical composition comprising a compound of formula Ia′, Ib′, Ic′, or Id′ or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula Ia′, Ib′, Ic′, or Id′ or a salt thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A and 1B show the anti-prion activities produced by representative compounds. The bottom line in FIG. 1B indicates that the reduction in spots is due to actual anti-prion activity and not just a lack of cells.

FIG. 2 shows sephin 1 treatment attends the EAE disease severity. N=7 mice.

FIG. 3A shows data for representative compounds in the tail-flick assay of Example 134. FIG. 3B shows data on the combination of BC1-45-1 with morphine and Table X shows the analysis of the analgesic interaction between guanabenz and morphine. FIG. 3C shows the effect of combination therapy on drug potency.

FIGS. 4A-4I and 4K-4X show data for representative compounds and control compounds in the cell viability assay of Example 134. Viability of HeLa cells was assessed by the ability to reduce WST-8 into formazan, following treatments with tunicamycin for 48 hours, with or without the indicated concentrations of E-guanabenz or the test compound. Data are means±SEM(n=3). *P<0.05.

FIG. 5A provides data from the assay of Example 135 for compound BC1-55-1 showing that pretreatment (30 min) with compound BC1-55-1 can limit the hepatotoxicity of acetaminophen. FIG. 5B provides comparative data from the assay of Example 135 for treatment with N-acetyl cysteine.

FIG. 6A provides data from the assay of Example 135 for compound BC1-55-1 showing that delayed administration of compound BC1-55-1 reduces elevated levels of ALT following acetaminophen overdose. FIG. 6B provides comparative data from the assay of Example 135 for delayed treatment with N-acetyl cysteine.

FIG. 7 provides data from the assay of Example 135 for compound BC1-55-1 showing that treatment with compound BC1-55-1 can reduce the lipid peroxidation products (measured by TBARS assay) elevated by acetaminophen overdose.

FIG. 8A provides data from the assay of Example 135 for representative compounds of formulae 1a′, 1b′, 1c′, and 1d′ showing that the compounds reduce elevated levels of ALT following acetaminophen overdose. FIG. 8B provides TBARS data from the assay of Example 135 for acetaminophen overdose and effect of representative compounds of formulae 1a′, 1b′, 1c′, and 1d′ on elevated TBARS (lipid peroxidation products).

FIG. 9A provides data from the assay of Example 135 for compound BC1-45-1 (GA) showing that pretreatment (30 min) with compound BC1-45-1 can limit the hepatotoxicity of acetaminophen as measured by ALT levels. FIG. 9B provides data from the assay of Example 135 for compound BC1-45-1 showing that delayed administration of compound BC1-45-1 reduces elevated levels of ALT following acetaminophen overdose.

FIG. 10A provides data from the assay of example 135 for compound BC1-45-1 (GA) showing that combination of acetaminophen with low dose BC1-45-1 (GA) exhibited synergy in the analgesic activity as measured by the tail flick assay. FIG. 10B provides isobologram analysis of the data presented in FIG. 10A. FIG. 10C provides data from the assay of Example 135 for compound BC1-45-1 (GA) showing that combination of low dose BC1-45-1 with acetaminophen does not have any effect on the hypothermic effect of acetaminophen.

FIG. 11A provides data from the assay of example 136 for compounds SW1-SW32 showing the number of plaques formed. FIG. 11B provides data from the assay of example 136 for compounds SW1-SW32 showing the percent inhibition of plaque formation. FIG. 11c provides data from the assay of example 136 for compounds SW1-SW32 showing graphs of all compounds together.

DETAILED DESCRIPTION

The term “alkyl”, by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., C₁₋₆ means one to six carbons). Non limiting examples of “alkyl” include methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl and hexyl.

The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane (including straight and branched alkanes), as exemplified by —CH₂—, —CH(CH₃)—, —CH₂CH₂CH₂CH₂— and —CH(CH₃)CH₂CH₂—.

The term “halo” mean —F, —Cl, —Br or —I.

The term “haloalkyl” means an alkyl that is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) halo. Non limiting examples of “haloalkyl” include iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl 2,2-difluoroethyl and pentafluoroethyl.

The term “aryl” as used herein refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring systems (e.g. ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic. Such multiple condensed ring systems may be optionally substituted with one or more (e.g. 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aryl or a carbocycle portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.

The term “heteroaryl” as used herein refers to a 3-6 membered single aromatic ring that has at least one (e.g., 1, 2, 3 or 4) atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “heteroaryl” also includes 7-20 membered multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole. One preferred embodiment of “6-membered heteroaryl” is pyridine, 1,4-diazine, 1,3-diazine, 1,2-diazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine.

The term “heterocycle” refers to a saturated or partially unsaturated ring system radical having the overall having from 3-20 ring atoms that contain from one to ten heteroatoms selected from N, O, and S. Unless otherwise stated, a “heterocycle” ring can be a monocyclic, a bicyclic, spirocyclic or a polycylic ring system. Non limiting examples of “heterocycle” rings include pyrrolidine, piperidine, N-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1s,4s)-2-azabicyclo[2.2.2]octane, (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and the like. A “heterocycle” group can be attached to the remainder of the molecule through one or more ring carbons or heteroatoms.

The term “unsaturated heterocycle” means a single or bicyclic 3-10 membered ring system that has one or two double bonds and has at least one (e.g., 1, 2, 3 or 4) atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur. One preferred embodiment of “unsaturated heterocycle” is 2-imidazoline.

The term “cycloalkyl” refers to hydrocarbon ring system having 3 to 8 overall number of ring atoms and for a 3-5 membered cycloalkyl being fully saturated or having no more than one double bond between ring vertices and for a 6 membered cycloalkyl or larger being fully saturated or having no more than two double bonds between ring vertices. One preferred embodiment of “cycloalkyl” is cyclopropyl.

The terms “treat” and “treatment” refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, Parkinson's disease. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.

The phrase “effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.

“α2-adrenergic receptor” is a G protein-coupled receptor. There are three α2-adrenergic receptor subtypes, α_(2A), α_(2B) and α_(2C). All there subtypes are involved in the control of pain perception in mice. The antihypertensive (sedative) effect in mice is solely mediated by the a2A-receptor subtype. Compounds that show selective affinities towards 2B and/or 2C would remain of the analgesic activity without the undesirable antihypertensive or other side effects.

Endoplasmic Reticulum Stress

The compounds of the invention are also useful to reduce endoplasmic reticulum stress. Accordingly, the compounds are useful to treat diseases and conditions that are associated with undesirable endoplasmic reticulum stress. Such conditions include drug-induced toxicity, heavy metal-induced (e.g. cadmium, lead, copper, arsenic and mercury) toxicity, carbon monoxide poisoning, and cyanide poisoning. For a discussion of endoplasmic reticulum stress and drug-induced toxicity, please see F. Foufelle and B. Fromerty, Pharmacology Research & Perspectives, 2016, 4, 1-28, which is incorporated herein in its entirety. Other diseases and conditions that are associated with undesirable endoplasmic reticulum stress include diabetes, viral infection (e.g., HIV, HSV, HBV) and cancer (see F. Foufelle and B. Fromerty, Pharmacology Research & Perspectives, 2016, 4, 1-28; and J. Lin et al., Annu Rev Pathol., 2008, 3, 399-425, which are both incorporated herein in their entirety)

In one embodiment the invention provides a method for reducing endoplasmic reticulum stress in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof.

In one embodiment the invention provides a method for reducing drug-induced toxicity in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof. In one embodiment, the drug is acetaminophen, amiodarone, arsenic trioxide, bleomycin, bortezomib, cisplatin, clozapine, olanzapine, cyclosporine, diclofenac, efavirenz, erlotinib, furosemide, indomethacin, taxol, protease inhibitors (e.g. indinavir and ritonavir), sertraline, and thaosigargin. In one embodiment the invention provides a method for reducing drug-induced toxicity in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof in combination with the drug. In one embodiment the invention provides a composition comprising: 1) a drug that is associated with unwanted endoplasmic reticulum stress, 2) a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof, and 3) a pharmaceutically acceptable carrier.

In one embodiment the invention provides a method for reducing heavy metal-induced toxicity in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof.

In one embodiment the invention provides a method for treating carbon monoxide poisoning in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof.

In one embodiment the invention provides a method for treating cyanide poisoning in an animal comprising administering to the animal an effective amount of compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof.

It will be appreciated by those skilled in the art that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.

When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, the compound may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95 the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.

In one embodiment, the neurodegenerative disorder is Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Prion disease, Huntington's disease (HD) or multiple sclerosis (MS).

In one embodiment, the neurodegenerative disorder is Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Prion disease, or multiple sclerosis (MS).

In one embodiment, the neurodegenerative disorder is Parkinson's disease.

In one embodiment, the neurodegenerative disorder is Prion disease.

In one embodiment, the neurodegenerative disorder is multiple sclerosis.

The invention also provides a method for producing analgesia in an animal (e.g., a mammal, such as a human) comprising administering to the animal an effective amount of compound of formula Ia, Ib or Ic, or a pharmaceutically acceptable salt thereof.

The invention provides a compound of formula Ia, Ib or Ic or a pharmaceutically acceptable salt thereof for use in producing analgesia in an animal.

The invention provides the use of a compound of formula Ia, Ib or Ic or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for producing analgesia in an animal.

In one embodiment, the animal is morphine dependent and/or morphine tolerant.

In one embodiment, the method for producing analgesia further comprises administering morphine to the animal.

In one embodiment, the analgesia is produced for synergy in antinociception with reduced sedation or cardiovascular effects.

In one embodiment, the animal is administered with an effective amount of compound of formula Ia, or a pharmaceutically acceptable salt thereof.

In one embodiment, the animal is administered with an effective amount of compound of formula Ib, or a pharmaceutically acceptable salt thereof.

In one embodiment, the animal is administered with an effective amount of compound of formula Ic, or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound administered in the method for treating Parkinson's disease is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl;

at least one of R¹, R², R³, R⁴, and R⁵ is Cl or Br;

and the group

In one embodiment, the compound administered in the method for treating Parkinson's disease is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the compound administered in the method for treating Prion disease is a compound of formula Ia or Ib:

or a pharmaceutically acceptable salt thereof;

i) wherein the compound of formula Ia:

ring A is phenyl;

the group

ii) wherein the compound of formula Ib:

ring A is phenyl;

the group

In one embodiment, the compound administered in the method for treating Prion disease is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the compound administered in the method for treating multiple sclerosis is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl;

at least one of R¹, R², R³, R⁴, and R⁵ is Cl or Br;

and the group

In one embodiment, the compound administered in the method for treating multiple sclerosis is

or a pharmaceutically acceptable salt.

In one embodiment, the compound administered in the method for producing analgesia is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl;

R¹ is not hydrogen;

R⁵ is not hydrogen;

and the group

In one embodiment, the compound administered in the method for producing analgesia is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

The invention provides a method for modulating (e.g., increasing or decreasing) the activity of α2-adrenergic receptor in vivo or in vitro comprising contacting the receptor with an effective amount of compound of formula Ia, Ib or Ic, or a pharmaceutically acceptable salt thereof.

In one embodiment, the α2-adrenergic receptor is α_(2B)-adrenergic receptor and or α_(2C)-adrenergic receptor.

In one embodiment, the invention also provides novel compounds of formula Ia, Ib or Ic, which are compounds of the invention.

In one embodiment, the compound is a compound of formula Ia, Ib or Ic, or a pharmaceutically acceptable salt thereof, provided that the compound is not:

In one embodiment, the compound is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof;

provided that the compound is not:

In one embodiment, the compound is a compound of formula Ib:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is a compound of formula Ic:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein X is O or S.

In one embodiment, the compound is a compound of formula Id:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl or 6-membered heteroaryl;

R¹ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN;

R² is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN;

R³ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN;

R⁴ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN;

R⁵ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN;

R^(L) is C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₈ cycloalkyl;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(f))₂, oxo, —NO₂ or —CN;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

R⁸ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN;

X is ═O, ═S or ═N—R^(x); wherein R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In one embodiment, the compound is a compound of formula Ie:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl or 6-membered heteroaryl;

R¹ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN;

R² is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN;

R³ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN;

R⁴ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN;

R⁵ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN;

ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(y), —SR^(y), —N(R^(y))₂, —NO₂ or —CN;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(f))₂, oxo, —NO₂ or —CN;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

R⁸ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN;

X is ═O, ═S or ═N—R^(x); wherein Rx is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g)groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(y) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(y) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In one embodiment, the compound is a compound of formula Ig:

or a pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl or 6-membered heteroaryl;

R¹ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN;

R² is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —N;

R³ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN;

R⁴ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN;

R⁵ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(f))₂, oxo, —NO₂ or —CN;

L is C₁₋₄ alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C₃₋₈ cycloalkyl;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

ring Z is heteroaryl or unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In one embodiment, ring A is phenyl.

In one embodiment, R¹ is hydrogen, —F, —Cl, —Br, —I or C₁₋₄ alkyl.

In one embodiment, R¹ is hydrogen, —F, —Cl, —Br, —I or —Me.

In one embodiment, R² is hydrogen or —Cl.

In one embodiment, R³ is hydrogen, —F, —Cl, or —OR^(c); R^(c) is hydrogen, or C₁₋₄ alkyl that is optionally substituted with aryl or heteroaryl.

In one embodiment, R³ is hydrogen, —F, —Cl, —OH, —OCH₃, or —OCH₂Ph.

In one embodiment, R⁴ is hydrogen, or —Cl.

In one embodiment, R⁵ is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, —F, —Cl, —Br, —I, —OR^(e), —N(R^(e))₂ or —NO₂.

In one embodiment, R⁵ is hydrogen, —Me, —CF₃, —F, —Cl, —Br, —I, —OH, —NH₂ or —NO₂.

In one embodiment, at least one of R¹, R², R³, R⁴ and R⁵ is not hydrogen.

In one embodiment, at least two of R¹, R², R³, R⁴ and R⁵ are hydrogen.

In one embodiment, the group

is selected from the group consisting of:

In one embodiment, L is

In one embodiment, L is

In one embodiment, ring Y is

In one embodiment, R⁶ is hydrogen or —CH₃.

In one embodiment, R⁷ is hydrogen or —CH₃.

In one embodiment, R⁸ is hydrogen or —CH₃.

In one embodiment, X is ═N—R^(x); and R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN.

In one embodiment, R^(x) is hydrogen or —CH₃.

In one embodiment, R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form an unsaturated heterocycle.

In one embodiment, R⁷ is hydrogen; R^(x) and R⁸ taken together with the carbon and nitrogen to which they are attached form

In one embodiment, wherein X is ═O or ═S.

In one embodiment, R⁶, R⁷, R⁸ and R^(x) are hydrogen.

In one embodiment, wherein R⁶ and R⁷ are hydrogen; R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form

In one embodiment, L is —CH₂—, or —CH(CH₃)—.

In one embodiment, R⁷ is hydrogen; ring Z is

In one embodiment, the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

In one embodiment, the compound is a compound of formula Ia′, which is a compound of formula Ij:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is a compound of formula Ia′, which is a compound of formula Ik:

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a method for treating A neurodegenerative disorder in an animal (e.g., a mammal, such as a human) comprising administering to the animal an effective amount of compound of formula Ia, Ib or Ic:

or a pharmaceutically acceptable salt thereof;

i) wherein the compound of formula Ia:

ring A is phenyl or 6-membered heteroaryl;

R¹ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN;

R² is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN;

R³ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN;

R⁴ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN;

R⁵ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN;

L is selected from the group consisting of:

—CH₂CH₂—

R^(L) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₈ cycloalkyl;

ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(y), —SR^(y), —N(R^(y))₂, —NO₂ or —CN;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(f))₂, oxo, —NO₂ or —CN;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

R⁸ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN;

X is ═O, ═S or ═N—Rx; wherein R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(y) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(y) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

ii) wherein the compound of formula Ib:

ring A is phenyl or 6-membered heteroaryl;

R¹ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN;

R² is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN;

R³ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN;

R⁴ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN;

R⁵ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN;

R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(a))₂, oxo, —NO₂ or —CN;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

R⁸ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN;

R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN;

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

iii) wherein the compound of formula Ic:

ring A is phenyl or 6-membered heteroaryl;

R¹ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN;

R² is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN;

R³ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN;

R⁴ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN;

R⁵ is absent, hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN;

L is C₁₋₄ alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C₃₋₈ cycloalkyl;

R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN;

ring Z is heteroaryl or unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; —NO₂ or —CN:

each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

In one embodiment, the compound of formula Ia′, Ib′, Ic′, or Id′ is a compound of formula Ia, Ib, or Ic.

In one embodiment, the invention provides a novel compound shown in the following table, or a free base or a salt thereof. The invention also provides a method for treating a neurodegenerative disorder in an animal comprising administering to the animal an effective amount of compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof. The invention also provides a method for producing analgesia in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof.

The invention also provides a method for reducing endoplasmic reticulum stress in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof.

The invention also provides a method for reducing drug-induced toxicity in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof.

The invention also provides a method for reducing drug-induced toxicity in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof in combination with the drug.

The invention provides a composition comprising: 1) a drug that is associated with unwanted endoplasmic reticulum stress, 2) a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof, and 3) a pharmaceutically acceptable carrier.

The invention also provides a method for reducing heavy metal-induced toxicity in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof in combination with the drug.

The invention also provides a method for treating carbon monoxide poisoning in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof.

The invention also provides a method for treating cyanide poisoning in an animal comprising administering to the animal a compound shown in the following table, or a free base or a pharmaceutically acceptable salt thereof.

NUMBER EXAMPLE MW STRUCTURE BC1-45-1 E-GA  1 291.13

BC1-55-1 Z-GA  55 291.13

BC1-167-1 Metabolite  2 307.13

BC1-171-1  56 307.13

BC1-189-1  3 291.13

BC1-236-1  4 291.13

BC1-242-2  27 230.09

BC1-252-2  29 232.11

BC1-256-2  28 204.06

BC1-259-2  30 245.11

BC1-262-1  26 268.53

BC1-272-1  5 270.72

BC1-282-1  6 325.58

BC1-283-1  7 291.13

BC1-295-1  8 222.24

BC1-297-1  9 301.14

BC1-299-1  10 256.69

BC2-3-1  11 236.27

BC2-5-1  12 274.68

BC2-7-1  13 291.13

BC2-9-1  14 256.69

BC2-11-1  15 240.23

BC2-13-1  16 256.69

BC2-17-1  17 274.68

BC2-19-1  18 274.68

BC2-25-1  19 286.71

BC2-27-1  20 250.30

BC2-35-1  21 335.58

BC2-45-1  22 324.69

BC2-47-1  23 380.04

BC2-55-2  31 413.98

BC2-57-2  24 301.69

BC2-61-1  32 211.65

BC2-61-2  32 177.21

BC2-59-2  25 272.69

BC1-267-2  57 270.12

JM1-111-2 112 212.25

JM1-113-2 113 231.67

JM1-115-2 114 248.12

JM1-121-2 115 207.29

JM1-125-2 116 258.68

JM1-127-2 117 337.03

JM1-129-2 118 229.30

JM1-135-2 119 197.23

JM1-141-2 120 231.08

JM1-143-2 121 319.98

JM1-175-2 122 286.08

JM1-177-2 123 250.14

JM1-179-2 124 225.18

JM1-185-2 125 274.68

JM1-191-2 126 258.22

JM1-195-2 127 254.26

JM1-217-2 128 228.07

JM1-221-2  33 324.68

JM1-223-2  34 308.23

JM1-257-2  35 224.69

JM1-285-2 130 270.11

JM2-59-2  36 225.72

JM2-63-2  37 261.10

JM2-67-2  38 337.20

JM2-83-2  39 293.57

JM2-85-2  40 252.74

JM2-87-2  41 229.10

JM2-89-2  42 304.13

JM2-91-2  43 293.57

JM2-95-2  44 277.12

JM2-97-2  45 266.55

JM2-101-2  46 243.13

JM2-103-2  47 260.67

JM2-109-2  48 348.58

JM2-111-2  49 382.48

JM2-113-2  50 259.13

JM2-115-2  51 242.68

JM2-131-2  52 327.13

JM2-133-2  53 273.16

JM2-171-2  58 373.01

JM2-175-2 131 435.09

JM2-185-2 132 233.09

JM2-191-2  54 303.58

JM2-195-2 133 397.25

JM2-233-2 129 280.32

JM2-255-2  60 307.60

JM2-257-2  61 266.77

JM2-263-2  62 318.15

JM2-265-2  63 287.18

JM2-271-2  64 243.13

JM2-275-2  65 292.01

JM2-279-2  66 168.21

JM2-287-2  67 282.54

JM2-289-2  59 387.04

JM3-11-2  68 291.13

JM3-13-2  69 267.24

JM3-17-2  70 238.24

JM3-27-2  71 248.10

JM3-29-2  72 292.12

JM3-57-2  73 335.58

JM3-63-2  74 332.78

JM3-67-2  75 307.17

JM3-81-2  76 287.74

JM3-89-2  77 298.77

JM3-99-2  78 306.41

JM3-131-2  79 227.08

JM3-141-2  80 358.24

JM3-149-2  81 293.57

JM3-151-2  82 328.02

JM3-153-2  83 307.60

JM3-155-2  84 342.04

JM3-161-2  85 415.10

JM3-179-2  86 229.10

JM3-181-2  87 243.13

JM3-183-2  88 348.14

JM3-191-2  89 311.16

JM3-195-2  90 311.16

JM3-197-2  91 297.13

JM3-199-2  92 297.13

JM3-201-2  93 331.58

JM2-203-2  94 280.68

JM3-205-2  95 345.60

JM3-207-2  96 294.71

JM3-209-2  97 311.16

JM3-211-2  98 297.14

JM3-213-2  99 276.72

JM3-215-2 100 262.69

JM3-219-2 101 278.53

JM3-221-2 102 217.62

JM3-223-2 103 234.08

JM3-225-2 104 325.53

JM3-227-2 105 233.09

JM3-239-2 106 305.15

JM3-255-2 107 352.05

JM3-257-2 108

JM2-233-2 109

JM2-169-2 110

Processes and intermediates useful for preparing compounds of formula Ia′, Ib′, Ic′, or Id′ are provided as further embodiments of the invention and are illustrated by the following procedures in which the meanings of the generic radicals are as given above unless otherwise qualified.

Compounds of formula Ia′, Ib′, Ic′, or Id′ may be prepared by the process illustrated in Schemes a and b.

-   Schemes a and b. General synthetic routes to representative     compounds of formula I.

(1a) The aldehyde (1 equivalent), aminoguanidine bicarbonate (1 equivalent) and AcOH (2 equivalents) in EtOH was refluxed for 12 hours. After cooling at room temperature, the final compound was recovered as a precipitate after filtration. If it did not precipitate, a crude reaction mixture was evaporated under vacuum and triturated with dry Et₂O before filtration. The precipitate was recrystallized from Ethanol to give the desired compound. The yields were around 70%-90%.

(1b) The aldehyde (1 equivalent), 2-hydrazonoimidazolidine hydrochloride (1 equivalent) and AcOH (few drops) in EtOH was refluxed for 12 hours. After cooling at room temperature, the final compound was recovered as a precipitate after filtration. If it did not precipitate, a crude reaction mixture was evaporated under vacuum and triturated with dry Et₂O before filtration. The precipitate was recrystallized from Ethanol to give the desired compound. The yields are all around 70%-90%.

In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula Ia, Ib or Ic can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, administration of a compound of formula Ia, Ib or Ic as a pharmaceutically acceptable acid or base salt may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.

The compounds of formula Ia, Ib or Ic can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.

Thus, the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various the other ingredients enumerated above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.

Useful dosages of the compounds of formula Ia, Ib or Ic can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.

The amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

The invention will now be illustrated by the following non-limiting Examples. The compounds identified in Preperative Examples 1-25 are intermediate compounds that can be used to prepare compounds of formula Ia′, Ib′, Ic′, or Id′.

All commercial reagents and solvents were used as provided. Flash chromatography was performed with Ultra Pure silica gel or with RediSep Rf silica gel columns on a Teledyne ISCO CombiFlash Rf system using the solvents as indicated. Nuclear magnetic resonance spectra were recorded on a Varian 600 MHz with Me₄Si or signals from residual solvent as the internal standard for ¹H and ¹³C. Chemical shifts are reported in ppm, and signals are described as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), brs (broad singlet), and dd (double doublet). Values given for coupling constants are first order. High resolution and low resolution mass spectra were recorded on an Agilent TOF II TOF/MS instrument equipped with an ESI interface. Analysis of sample purity was performed on an Agilent 1200 Infinity series HPLC system with a Phenomenex Gemini C18 column (5 μm, 4.6 mm×250 mm). HPLC conditions were the following: solvent A=water with 0.1% fomic acid , solvent B=MeCN with 0.1% fomic acid; flow rate=1.0 mL/min. Compounds were eluted with a gradient of from 5% to 95% B in 15 min, then from 95% to 5% B in 5 min. Purity was deter ed by the absorbance at 254 nm. All tested compounds have a purity of ≥95%.

PREPERATIVE EXAMPLES Preperative Example 1 (E)-N-butyl-1-(2,6-difluorophenyl)methanimine (JM2-209-2)

To a solution of 2,6-difluorobenzaldehyde (500 mg, 3.52 mmol) in toluene (5 mL) was added p-TsOH (13.3 mg, 2 mol %) and n-butyl amine (257 mg, 3.52 mmol). The reaction mixture was stirred at room temp for 30 h. The resulting solution was diluted with toluene (10 mL), washed with 5% NaHCO₃ solution, water followed by brine. The organic layer was dried over Na₂SO₄ and evaporated to get the final compound as yellow oil (80%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.41 (s, 1H), 7.51-7.44 (m, 1H), 7.12 (t, 2H, J=8.8 Hz), 3.56 (t, 2H, J=7.0 Hz), 1.58-1.53 (m, 2H), 1.33-1.25 (m, 2H), 0.87 (t, 3H, J=7.0 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 162.13, 160.44, 151.20, 132.52, 113.75, 112.71, 112.68, 112.58, 112.54, 62.27, 32.78, 20.22, 14.08. ESI-MS (M+H)⁺ 198.12.

Preperative Example 2 1-(2,6-dichlorophenyl)propan-1-ol (JM2-213-2)

2,6-dichlorobenzaldehyde (1.0 g, 5.7 mmol) was dissolved in tetrahydrofuran (10 mL). The solution was cooled to −10° C., added ethyl magnesium chloride solution (3.6 mL, 7.2 mmol) dropwise under argon. The reaction mixture was allowed to room temp, stirred for overnight and quenched with sat. NH₄Cl solution at 0° C. The compound was extracted with ether and washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude was purified by silica gel chromatography using 0-20% ethyl acetate in hexanes. Colorless oil (43%). ¹H NMR (cdcl₃, 600 MHz) δ7.26 (d, 2H, J=8.2 Hz), 7.11 (t, 1H, J=8.2 Hz), 5.32 (t, 1H, J=8.2 Hz), 2.11-2.02 (m, 2H), 1.99-1.90 (m, 1H), 0.97 (t, 3H, J=7.6 Hz). ¹³C NMR (150 MHz, cdcl₃) δ 137.83, 134.24, 129.31, 128.70, 73.56, 28.66, 10.50. ESI-MS (M-H)⁻203.01.

Preperative Example 3 (E)-N-butyl-1-(2,6-diethylphenyl)methanimine (JM2-215-2)

(E)-N-butyl-1-(2,6-difluorophenyl)methanimine (300 mg, 1.52 mmol) was dissolved in tetrahydrofuran (8 mL). The solution was cooled to −10° C., added ethyl magnesium chloride solution (1.7 mL, 3.4 mmol) dropwise under argon. The reaction mixture was allowed to room temp, stirred for overnight and quenched with sat. NaHCO₃ solution. The compound was extracted with ethyl acetate and washed with brine, dried over Na₂SO₄, and concentrated in vacuo to get final compound as colorless oil (91%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.60 (s, 1H), 7.18 (t, 1H, J=7.6 Hz), 7.03 (d, 2H, J=7.6 Hz), 3.56 (t, 2H, J=6.5 Hz), 2.66 (q, 4H, J=7.6 Hz), 7.61 (d, 2H, J=8.2 Hz), 1.61-1.54 (m, 2H), 1.39-1.31 (m, 2H), 1.06 (t, 6H, J=7.6 Hz), 0.89(t, 3H, J=7.6 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 160.43, 143.19, 133.89, 129.20, 127.09, 61.73, 33.13, 26.38, 20.40, 16.22, 14.15. ESI-MS (M+H)⁺ 218.19.

Preperative Example 4 1-(2,6-dichlorophenyl)propan-1-one (JM2-223-2)

To a stirred solution of 1-(2,6-dichlorophenyl)propan-1-ol (200 mg, 0.98 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (582 mg, 1.37 mmol) and stirring was continued for 3 h. The reaction mixture was filtered on celite pad and washed with dichloromethane. The filtrate was washed with sat. NaHCO₃, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as colorless oil (81%). ¹H NMR (dmso-d_(6, 600) MHz) δ 7.30 (d, 1H, J=7.0 Hz), 7.25 (t, 2H, J=7.0 Hz), 2.85 (q, 2H, J=7.0 Hz), 1.22 (t, 6H, J=7.0 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 203.05, 140.01, 130.34, 130.31, 128.01, 37.02, 7.25. ESI-MS (M)⁺ 201.99.

Preperative Example 5 2,6-diethylbenzaldehyde (JM2-227-2)

A solution of (E)-N-butyl-1-(2,6-diethylphenyl)methanimine (200 mg, 0.92 mmol) in H₂SO_(4/)H₂O (2:8) was refluxed for 2 h. The reaction mixture was cooled to room temp, extracted with ethyl acetate washed with water followed by 5% NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as colorless oil (80%). ¹H NMR (dmso-d_(6, 600) MHz) δ 10.49 (s, 1H), 7.41 (t, 1H, J=7.6 Hz), 7.15 (d, 2H, J=7.6 Hz), 2.88 (q, 4H, J=7.0 Hz), 1.12 (t, 6H, J=7.6 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 194.82, 146.94, 133.61, 131.99, 128.61, 26.24, 17.06. ESI-MS (M+H)⁺ 163.11.

Preperative Example 6 Ethyl 2-(2-chloro-6-nitrophenyl)-2-cyanoacetate (JM2-231)

To a suspension of NaH (409 mg, 17.0 mmol, 60% dispersion in oil) in DMSO (8 mL) at 0° C. was added ethyl cyanoacetate (1.96 g, 17.0 mmol) slowly, and the mixture was stirred at room temp for 30 min before 1-chloro-2-fluoro-3-nitrobenzene (1.5 g, 8.54 mmol) in DMSO (8 mL) was added. The resulting solution was stirred at 90° C. for overnight and quenched by adding 2 N HCl (10 mL). After extraction with the EtOAc the combined organics were washed with NaHCO₃, brine, dried over Na₂SO₄, and concentrated in vacuo to leave brown oil. The crude material was used for next step without further purification. ESI-MS (M-H)⁻267.02.

Preperative Example 7 2-(2-chloro-6-nitrophenyl)acetonitrile (JM2-237-2)

A solution of ethyl 2-(2-chloro-6-nitrophenyl)-2-cyanoacetate (2.1 g, 8.16 mmol) in DMSO/H₂O (9:1) mixture was stirred at 120° C. for 16 h before being quenched with water. The aqueous solution was extracted using EtOAc (2×30 mL). The combined organics were washed with water and brine, dried over Na₂SO₄, and concentrated in vacuo. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as yellow solid (80%, over 2 steps). ¹H NMR (dmso-d₆, 600 MHz) δ 8.06 (d, 1H, J=8.2 Hz), 7.97 (d, 1H, J=8.2 Hz), 7.68 (t, 1H, J=8.2 Hz), 4.19 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 150.71, 136.11, 135.27, 131.31, 124.73, 124.34, 116.95, 19.35. ESI-MS (M-H)⁻194.99.

Preperative Example 8 Methyl 2-(2-chloro-6-nitrophenyl)acetate (JM2-241-2)

A solution of 2-(2-chloro-6-nitrophenyl)acetonitrile (300 mg, 1.52 mmol) in 45% sulfuric acid in water and methanol (5 mL) was refluxed for overnight. The reaction mixture was evaporated and extracted with EtOAc and washed with sat. NaHCO₃ solution followed by brine. The organic layer was dried over Na₂SO₄ and evaporated. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as colorless oil (50%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.03 (d, 1H, J=8.2 Hz), 7.91 (d, 1H, J=8.2 Hz), 7.60 (t, 1H, J=8.2 Hz), 4.08 (s, 2H), 3.64 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 169.60, 150.93, 136.59, 134.75, 130.15, 127.85, 124.35, 65.64, 35.49. ESI-MS (MH)⁺ 229.01.

Preperative Example 9 2-(methylthio)-1,4,5,6-tetrahydropyrimidine hydroiodide (JM2-243-2)

A solution of tetrahydropyrimidine-2(1H)-thione (1.5 g, 12.9 mmol) and methyl iodide (2.2 g, 15.48 mmol) in 15 mL of methanol was refluxed for 6 h. The solvent was evaporated, washed with ether to yield final product as light yellow solid (98%). ¹H NMR (dmso-d₆, 600 MHz) δ 9.51 (br s, 2H), 3.36 (t, 4H, J=5.8 Hz), 2.57 (s, 3H), 1.90-1.85 (m, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 163.33, 40.48, 18.61, 13.72. ESI-MS (M+H)⁺ 131.06.

Preperative Example 10 2-hydrazonohexahydropyrimidine hydrochloride (JM2-251-2)

A solution of 2-(methylthio)-1,4,5,6-tetrahydropyrimidine hydroiodide (1.0 g, 3.87 mmol) was cooled to 0° C. in ethanol and 50-60% hydrazine hydrate (434 mg, 13.56 mmol) was added in one portion under argon. The resulting mixture was stirred for 1 h and then heated to reflux for 4 h. The solution was evaporated under vacuum followed by azeotropy with water (3×10 mL). The residue was acidified with 10 mL of 1 N HCl and the solvent was removed in vacuum to obtain product as yellow powder (96%). ¹H NMR (D₂O, 600 MHz) δ 3.20 (t, 4H, J=5.8 Hz), 1.82-1.77 (m, 2H). ¹³C NMR (150 MHz, D₂O) δ 37.88, 19.50. ESI-MS (M+H)⁺ 115.09.

Preperative Example 11 1-(2,6-dichlorophenyl)-2-nitroethan-1-ol (JM3-3-2)

To a stirred solution of 2,6-dichlorobenzaldehyde (875 mg, 5.0 mmol) in methanol (4 mL) was added nitromethane (305 mg, 5.0 mmol) and stirred vigorously. To this solution was added 1 mL of 10.5 mol/L KOH solution was added dropwise in an ice bath and stirring was continued for 15 min at 0° C. followed by dropwise addition of Conc. HCl (3 mL). The reaction mixture was extracted with EtOAc (2X), washed with water, brine and dried over Na₂SO₄. The organics were evaporated and crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as colorless oil (85%). ¹H NMR (dmso-d₆, 600 MHz) δ 7.47 (d, 2H, J=7.6 Hz), 7.36 (t, 1H, J=8.2 Hz), 6.33 (d, 1H, J=4.7 Hz), 6.09-6.03 (m, 1H), 5.04 (dd, 1H, J=9.9 Hz), 4.92 (dd, 1H, J=12.9 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 134.85, 134.37, 131.13, 130.13, 78.58, 67.63. ESI-MS (M-H)⁻233.97.

Preperative Example 12 (E)-1,3-dichloro-2-(2-nitrovinyl)benzene (JM3-15-2)

To a stirred solution of 1-(2,6-dichlorophenyl)-2-nitroethan-1-ol (900 mg, 3.82 mmol) and mesyl chloride (523 mg, 4.57 mmol) in tetrahydrofuran (10 mL) was added triethylamine (807 mg, 2.1 mmol) dropwise at 0° C. After 1.5 h, saturated ammonium chloride was added to the reaction mixture and aqueous phase was extracted with EtOAc. The extract was washed with 1N HCl, NaHCO₃ and brine, dried over Na₂SO₄, filtrated and concentrated in vacuo. The residual solid was purified by recrystallization from EtOAc and hexane to obtain final compound as light yellow powder (81%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.12 (d, 1H, J=14.1 Hz), 8.02 (d, 1H, J=14.1 Hz), 7.63 (d, 2H, J=8.2 Hz), 7.51 (t, 1H, J=8.2 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 144.02, 135.02, 132.90, 132.64, 129.71, 127.98. ESI-MS (M)⁺ 216.95.

Preperative Example 13 2-amino-1-(2,6-dichlorophenyl)ethan-1-ol (JM3-23-2)

To a stirred solution of tin (II)chloride dehydrate (1.29 mg, 5.72 mmol) in ethanol (6 mL) and 0.8 mL of Conc. HCl was added 1-(2,6-dichlorophenyl)-2-nitroethan-1-ol (3 potions over 15 min) at 70° C. After the addition the solution was refluxed for 2.5 h. To this reaction mixture was added 6 mL of water then stirred at 10-15° C. for 20 min. The solution was basified with 2 N NaOH (pH ˜12) followed by evaporation of ethanol in vacuo. The residue was dissolved in EtOAC washed with water, brine and dried over Na₂SO₄. The crude was recrystallized from EtOAc and hexane to obtain final compound as light yellow solid (72%). ¹H NMR (dmso-d₆, 600 MHz) δ 7.37 (d, 2H, J=7.6 Hz), 7.23 (t, 1H, J=7.6 Hz), 5.44 (s, 1H), 5.18-5.13 (m, 1H), 3.04 (dd, 1H, J=9.9 Hz), 2.70 (dd, 1H, J=12.9 Hz), 1.52 (br s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 138.16, 134.61, 129.85, 129.70, 73.00, 45.59. ESI-MS (M+H)⁺ 206.01.

Preperative Example 14 3,5-dichloro-4-formylphenyl trifluoromethanesulfonate (JM3-61-2)

To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (500 mg, 2.62 mmol) and pyridine (498 mg, 2.4 mmol) in dichloromethane at 0° C. was added dropwise trifluoromethanesulfonic anhydride (1.57 g, 5.24 mmol). The solution was allowed to warm to room temperature while stirring overnight. The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (10 mL). The resulting mixture was extracted with water (20 mL) and EtOAc (2×20 mL) followed by washing with brine, dried over Na₂SO₄, filtered and evaporated. The residue was purified by silica gel chromatography using 10% ethyl acetate in hexanes to yield yellow oil (42%). ¹H NMR (dmso-d₆, 600 MHz) δ 10.29 (s, 1H), 8.01 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 189.07, 150.63, 136.78, 131.63, 123.98, 119.64, 109.99. ESI-MS (M+H)⁺ 321.07.

Preperative Example 15 (E)-4-((2-carbamimidoylhydrazono)methyl)-3,5-dichlorophenyl trifluoromethanesulfonate (JM3-65-1)

A solution of 3,5-dichloro-4-formylphenyl trifluoromethanesulfonate (300 mg, 0.93 mmol) and amino guanidine bicarbonate (127 mg, 0.93 mmol) in ethanol was refluxed for overnight. The reaction mixture was evaporated, followed by trituration with diethyl ether yielded crude compound. The crude material was used for next step without further purification.

Preperative Example 16 (E)-N-butyl-1-(2-chloro-6-fluorophenyl)methanimine (JM3-71-2)

To a solution of 2-chloro-6-fluorobenzaldehyde (1.00 g, 6.30 mmol) in toluene (10 mL) was added p-TsOH (23.0 mg, 2 mol %) and n-butyl amine (506 mg, 6.93 mmol). The reaction mixture was stirred at room temp for 30 h. The resulting solution was diluted with toluene (10 mL), washed with 5% NaHCO₃ solution, water followed by brine. The organic layer was dried over Na₂SO₄ and evaporated to get the final compound as light yellow oil (80%). ¹H NMR (dmso-d₆, 400 MHz) δ 8.45 (s, 1H), 7.46 (q, 1H, J=8.2 Hz), 7.37 (d, 1H, J=8.2 Hz), 7.27 (t, 1H, J=9.3 Hz) 3.60 (t, 2H, J=7.0 Hz), 1.59 (quin, 2H, J=7.0 Hz), 1.32 (sex, 2H, J=7.6 Hz), 0.89 (t, 3H, J=7.0 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 161.79, 160.10, 154.14, 134.15, 132.19, 126.33, 123.19, 115.93, 61.88, 32.69, 20.15, 14.08. ESI-MS (M+H)⁺ 214.07.

Preperative Example 17 (E)-N-butyl-1-(2-chloro-6-ethylphenyl)methanimine (JM3-73-2)

To a solution of (E)-N-butyl-1-(2-chloro-6-fluorophenyl)methanimine (500 mg, 2.33 mmol) in tetrahydrofuran (12 mL) at −10° C. was added ethyl magnesium chloride solution (1.28 mL, 2.57 mmol) dropwise under argon. The reaction mixture was allowed to room temp, stirred for overnight and quenched with sat. NaHCO₃ solution. The compound was extracted with ethyl acetate and washed with brine, dried over Na₂SO₄, and concentrated in vacuo to get final compound as light yellow oil (56%). ¹H NMR (dmso-d₆, 400 MHz) δ 8.56 (s, 1H), 7.32 (d, 2H, J=8.2 Hz), 7.24 (t, 1H, J=8.2 Hz), 3.60 (t, 2H, J=6.4 Hz), 2.79 (q, 2H, J=7.3 Hz), 1.60 (quin, 2H, J=7.0 Hz), 1.38 (sex, 2H, J=7.6 Hz), 1.09 (t, 3H, J=7.6 Hz), 0.91 (t, 3H, J=7.0 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 158.63, 145.89, 134.72, 133.08, 130.71, 128.95, 127.44, 61.58, 32.92, 26.29, 20.31, 16.19, 14.15. ESI-MS (M+H)⁺ 224.12.

Preperative Example 18 2-chloro-6-ethylbenzaldehyde (JM3-75-2)

A solution of (E)-N-butyl-1-(2-chloro-6-ethylphenyl)methanimine (100 mg, 0.92 mmol) in H₂SO_(4/)water (2:8) was refluxed for 3 h. The reaction mixture was cooled to room temp, extracted with ethyl acetate washed with water followed by 5% NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as light yellow oil (93%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.48 (s, 1H), 7.54 (t, 1H, J=7.6 Hz), 7.45 (d, 1H, J=8.2 Hz), 7.34 (d, 1H, J=7.6 Hz) 2.86 (q, 2H, J=7.6 Hz), 1.12 (t, 3H, J=7.6 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 193.01, 148.10, 136.89, 134.72, 131.07, 130.00, 128.76, 26.29, 16.29. ESI-MS (M-H)⁻ 167.02.

Preperative Example 19 (E)-N-butyl-1-(2-chloro-64-isopropylphenyl)methanimine (JM3-83-2)

To a solution of (E)-N-butyl-1-(2-chloro-6-fluorophenyl)methanimine (350 mg, 1.64 mmol) in tetrahydrofuran (8 mL) at −10° C. was added isopropyl magnesium bromide solution (1.8 mL, 1.8 mmol) dropwise under argon. The reaction mixture was allowed to room temp, stirred for overnight and quenched with sat. NaHCO₃ solution. The compound was extracted with ethyl acetate and washed with brine, dried over Na₂SO₄, and concentrated in vacuo to get final compound as light yellow oil (51%). ¹H NMR (dmso-d₆, 400 MHz) δ 8.55 (s, 1H), 7.35 (t, 2H, J=8.2 Hz), 7.30 (t, 1H, J=8.2 Hz), 3.57 (t, 2H, J=7.0 Hz), 3.47 (sep, 1H, J=7.0 Hz), 1.60 (quin, 2H, J=7.0 Hz), 1.38(sex, 2H, J=7.6 Hz), 1.13 (d, 6H, J=7.6 Hz), 0.91 (t, 3H, J=7.0 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 158.63, 145.89, 134.72, 133.08, 130.71, 128.95, 127.44, 61.58, 32.92, 26.29, 20.31, 16.19, 14.15. ESI-MS (M+H)⁺ 238.13.

Preperative Example 20 2-chloro-6-isopropylbenzaldehyde (JM3-87-2)

A solution of (E)-N-butyl-1-(2-chloro-6-isopropylphenyl)methanimine (120 mg, 0.50 mmol) in H₂SO_(4/)water (2:8) was refluxed for 2 h. The reaction mixture was cooled to room temp, extracted with ethyl acetate washed with water followed by 5% NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as light yellow color oil (98%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.56 (s, 1H), 7.63 (t, 1H, J=7.8 Hz), 7.57 (d, 1H, J=7.8 Hz), 7.49 (d, 1H, J=7.8 Hz) 2.86 (sep, 1H, J=6.8 Hz), 125 (d, 6H, J=6.8 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 194.05, 152.04, 135.62, 134.42, 131.70, 128.34, 126.07, 28.56, 24.07. ESI-MS (M)⁺ 182.04.

Preperative Example 21 (E)-N-butyl-1-(2,6-diisopropylphenyl)methanimine (JM3-95-2)

To a solution of (E)-N-butyl-1-(2,6-difluorophenyl)methanimine (500 mg, 2.50 mmol) in tetrahydrofuran (12 mL) at −10° C. was added ethyl magnesium chloride solution (5.0 mL, 5.0 mmol) dropwise under argon. The reaction mixture was allowed to room temp, stirred for overnight and quenched with sat. NaHCO₃ solution. The compound was extracted with ethyl acetate and washed with brine, dried over Na₂SO₄, and concentrated in vacuo to get final compound as light yellow color oil (60%). ¹H NMR (dmso-d₆, 400 MHz) δ 8.75 (s, 1H), 7.35 (t, 1H, J=7.8 Hz), 7.23 (d, 2H, J=7.5 Hz), 3.67 (t, 2H, J=6.6 Hz), 3.23 (sep, 2H, J=7.3 Hz), 1.67 (quin, 2H, J=7.0 Hz), 1.46 (sex, 2H, J=7.3 Hz), 1.21 (d, 12H, J=6.8 Hz), 0.99 (t, 3H, J=7.5 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 161.24, 146.69, 134.33, 129.14, 122.88, 61.55, 33.08, 29.39, 23.99, 20.43, 14.21. ESI-MS (M+H)⁺ 246.22.

Preperative Example 22 2,6-diisopropylbenzaldehyde (JM3-97-2)

A solution of (E)-N-butyl-1-(2,6-diethylphenyl)methanimine (200 mg, 0.92 mmol) in H₂SO_(4/)water (2:8) was refluxed for 2 h. The reaction mixture was cooled to room temp, extracted with ethyl acetate washed with water followed by 5% NaHCO₃ solution, brine, dried over Na₂SO₄ and concentrated in vacuo. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as light yellow oil (80%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.71 (s, 1H), 7.54 (t, 2H, J=7.8 Hz), 7.35 (d, 1H, J=7.8 Hz), 3.49 (sep, 2H, J=6.8 Hz), 1.25 (d, 12H, J=6.8 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 197.63, 149.07, 133.59, 132.65, 123.87, 28.67, 24.41. ESI-MS (M)⁺ 190.13.

Preperative Example 23 (2,6-bis(trifluoromethyl)phenyl)methanol (JM3-1352-2)

To a solution of KO^(t)Bt (1.3 g, 11.62 mmol) in THF at −70° C. was added 2,6-bis(trifluoromethyl)benzene (2.0 g, 9.3 mmol) dropwise over a period of 30 min. To this solution was added n-BuLi (18.6 mmol, 2.5 M in hexanes) dropwise for 30 min, stirring continued at −70° C. for 60 min. To this mixture was added Paraformaldehyde (61.2 g, 37.2 mmol) and stirring continued at −70° C. for 30 min, then allowed to room temperature for 3 h. The reaction mixture was poured into conc. HCl (2 mL) and ice water (60 mL) and stirred for 1 h, extracted with hexanes (3×10 mL) and washed with brine, dried over Na₂SO₄, and concentrated in vacuo to get final compound as dark brown oil (40%). ESI-MS (M)⁺ 244.03.

Preperative Example 24 2,6-bi s(trifluoromethyl)benzaldehyde (JM3-139-2)

To a stirred solution of (2,6-bis(trifluoromethyl)phenyl)methanol (300 mg, 1.2 mmol) in dichloromethane (5 mL) was added Dess-Martin periodinane (782 mg, 1.84 mmol) and stirring was continued at room temp for 3 h. The reaction mixture was filtered on celite pad and washed with dichloromethane. The filtrate was washed with sat. NaHCO₃, brine, dried over Na₂SO₄ and concentrated in vacuum. The crude was purified on silica gel chromatography using EtOAc and hexane to obtain final compound as light yellow oil (33%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.66 (s, 1H), 8.23 (d, 2H, J=8.0 Hz), 8.01 (t, 1H, J=7.8 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 193.64, 132.99, 131.35, 128.45, 128.13, 124.88. ESI-MS (M)⁺ 242.01.

Preperative Example 25 2-(2,6-dichlorophenyl)acetaldehyde (JM3-237-2)

To a stirred solution of (2,6-trichloro-phenyl)-acetonitrile (800 mg, 4.3 mmole) in 10 mL toluene at 0° C. was added DIBAL-H (3.34 mL of 25% w/w in hexane, 4.7 mmol) dropwise over a period of 30 min. The reaction mixture was allowed to room temp and stirred for overnight. The reaction was quenched by dropwise addition of 12 mL of 2 N HCl at 0° C. and was kept for 30 min at ambient temperature. Toluene layer was separated and aq. layer was extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated under vacuum to yield final compound as light yellow solid (72%). ¹H NMR (CDCl₃, 400 MHz) δ 9.74 (s, 1H), 7.36 (d, 2H, J=8.1 Hz), 7.20 (t, 1H, J=8.01 Hz), 4.11 (s, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 196.59, 136.10, 133.68, 129.81, 129.29, 128.21, 45.84.

Preperative Example Salubrinal (JM3-177-2 & JM3-189-2)

N-(2,2,2-trichloro-1-isothiocyanatoethyl)cinnamamide (400 mg, 1.2 mmol) was dissolved in 10 mL of tetrahydrofuran, added 8-amino quinoline (172. mg, 1.2 mmol). The reaction mixture was heated at 60° C. for overnight. The crude mixture was evaporated, extracted with water and ethyl acetate. The organic layer was washed with brine dried with Na₂SO₄. The solvent was evaporated and crude compound was purified on silica with 0-10% methanol in dichloromethane to yield final compound (52%). ¹H NMR (dmso-d₆, 600 MHz) δ 11.02 (s, 1H), 9.54 (d, 1H, J=9.4 Hz), 9.01 (d, 1H, d, J=6.4 Hz), 8.94 (d, 1H, d, J=4.1 Hz), 8.41 (d, 1H, d, J=7.0 Hz), 7.71 (d, 1H, d, J=8.2 Hz), 7.76-7.53 (m, 6H), 7.44-7.37 (m, 3H), 6.8 (d, 1H, J=15.8 Hz). ¹³C NMR (100 MHz, dmso-d6) δ 181.01, 164.84, 149.37, 141.40, 140.15, 137.20, 135.88, 135.13, 130.33, 129.48, 128.44, 128.21, 126.66, 123.30, 122.28, 121.49, 120.65, 101.88, 70.15. ESI-HRMS Calc m/z for C₂₁H₁₈Cl₃N₄OS 479.0261 (M+H)⁺, found 479.0257. HPLC 96.05% purity t_(R)=14.17 min.

EXAMPLES

Using the appropriately substituted starting materials, compounds of formula Ia, Ib or Ic in Examples 1-25 and 33-35 were prepared following the procedure as described above in Scheme 1a.

Using the appropriately substituted starting material, compounds of formula Ia, Ib or Ic in Examples 39-40, 42-44 and 47-54 were prepared following the procedure as described above in Scheme 1b.

Example 1 (E)-2-(2,6-dichlorobenzylidene)hydrazinecarboximidamide acetate (BC1-45-1)

White powder. ¹H NMR (DMSO-d₆, 600 MHz) δ 8.20(s, 1H), 7.48(d, 2H, J=6.0 Hz), 7.31(t, 1H, J=6.0 Hz), 6.85(brs, 4H), 1.82(s, 3H). ¹³C NMR (151 MHz, dmso) δ 174.67, 159.82, 139.25, 134.04, 131.45, 130.29, 129.56, 22.97. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 231.0199 Found 231.0212. HPLC 98.58% purity t_(R)=5.99 min.

Example 2 (E)-2-(2,6-dichloro-4-hydroxybenzylidene)hydrazinecarboximidamide acetate (BC1-167-1)

Light yellow powder. 1H NMR (600 MHz, cd3od) δ 8.31 (s, 1H), 6.84 (s, 2H), 1.92 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 177.83, 160.34, 156.27, 143.19, 135.41, 119.44, 116.43, 53.13, 47.99, 47.85, 47.71, 47.56, 47.42, 47.28, 47.14, 21.89. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 247.0148 Found 247.0149. HPLC 96.43% purity t_(R)=4.42 min.

Example 3 (E)-2-(3,4-dichlorobenzylidene)hydrazinecarboximidamide acetate (BC1-189-1)

White powder. ¹H NMR (600 MHz, dmso) δ 8.07 (s, 1H), 7.97 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 6.67 (brs, 4H), 1.84 (s, 3H). ¹³C NMR (151 MHz, dmso) δ 174.21, 160.16, 141.27, 137.50, 131.87, 130.98, 130.60, 127.97, 127.12, 40.37, 40.23, 40.09, 39.95, 39.81, 39.67, 39.53, 22.80. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 231.0199 Found 231.0215. HPLC 95.58% purity t_(R)=5.45 min.

Example 4 (E)-2-(2,4-dichlorobenzylidene)hydrazinecarboximidamide acetate (BC1-236-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.47 (s, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 1.92 (s, 3H). 13C NMR (151 MHz, cd3od) δ 178.37, 157.02, 142.09, 136.15, 134.40, 130.16, 129.17, 128.16, 127.38, 22.22. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 231.0199 Found 231.0214. HPLC 96.11% purity t_(R)=5.38 min.

Example 5 (E)-2-(2-chloro-6-methylbenzylidene)hydrazinecarboximidamide acetate (BC1-272-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.52 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 7.23 (d, J=7.2 Hz, 1H), 2.54 (s, 3H), 1.92 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 175.79, 156.63, 145.70, 139.81, 134.65, 130.00, 129.77, 129.71, 127.09, 22.44, 20.74. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 211.0745 Found 211.0755. HPLC 99.01% purity t_(R)=5.09 min.

Example 6 (E)-2-(2,3,6-trichlorobenzylidene)hydrazinecarboximidamide acetate (BC1-282-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.30 (s, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 1.94 (s, 3H). ¹³C NMR (151 MHz, cd3od) δ 179.07, 157.11, 141.76, 132.91, 132.83, 132.18, 132.04, 130.99, 129.30, 22.49. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 231.0199 Found 231.0206. HPLC 96.36% purity t_(R)=5.32 min.

Example 7 (E)-2-(3,5-dichlorobenzylidene)hydrazinecarboximidamide acetate (BC1-283-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.13 (s, 1H), 7.88 (s, 2H), 7.57 (s, 1H), 2.03 (s, 3H). ¹³C NMR (151 MHz, cd3od) δ 178.46, 157.04, 144.09, 137.46, 135.21, 129.18, 125.28, 22.26. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 264.9809 Found 264.9810. HPLC 97.25% purity t_(R)=5.53 min.

Example 8 (E)-2-benzylidenehydrazinecarboximidamide acetate (BC1-295-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.16 (s, 1H), 7.81 (s, 2H), 7.45 (s, 3H), 1.99 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.41, 156.29, 147.36, 133.65, 130.21, 128.39, 127.15, 22.78. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 163.0978 Found 163.0991. HPLC 96.38% purity t_(R)=2.29 min.

Example 9 (E)-2-(2-bromobenzylidene)hydrazinecarboximidamide acetate (BC1-297-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.62 (s, 1H), 8.25 (d, J=7.7 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 2.05 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 178.90, 156.55, 145.76, 132.89, 132.54, 131.49, 127.56, 127.50, 123.76, 48.00, 47.86, 47.72, 47.57, 47.43, 47.29, 47.15, 22.50. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 241.0083 Found 241.0087. HPLC 97.41% purity t_(R)=4.87 min.

Example 10 (E)-2-(2-chlorobenzylidene)hydrazinecarboximidamide acetate (BC1-299-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.71 (s, 1H), 8.33 (d, J=7.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 2.11 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 178.99, 156.53, 143.35, 133.97, 131.28, 131.01, 129.54, 127.17, 126.94, 48.00, 47.86, 47.72, 47.57, 47.43, 47.29, 47.15, 22.52. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 197.0589 Found 197.0593. HPLC 95.48% purity t_(R)=4.76 min.

Example 11 (E)-2-(2-methylbenzylidene)hydrazinecarboximidamide acetate (BC2-3-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.57 (s, 1H), 8.09 (d, J=7.2 Hz, 1H), 7.45 (t, J=6.8 Hz, 1H), 7.37 (t, J=7.6 Hz, 2H), 2.62 (s, 3H), 2.07 (s, 3H). ¹³C NMR (151 MHz, cd3od) δ 178.53, 156.08, 146.17, 137.34, 131.38, 130.50, 130.11, 126.27, 125.88, 22.30, 18.03. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 177.1135 Found 177.1147. HPLC 95.73% purity t_(R)=4.67 min.

Example 12 (E)-2-(2-chloro-6-fluorobenzylidene)hydrazinecarboximidamide acetate (BC2-5-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.52 (s, 1H), 7.59-7.50 (m, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.33 (t, J=9.2 Hz, 1H), 2.07 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.09, 161.87, 160.16, 156.60, 140.03, 134.51, 134.48, 131.37, 131.30, 125.80, 125.78, 120.09, 120.00, 114.96, 114.81, 22.51. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 215.0494 Found 215.0507. HPLC 95.39% purity t_(R)=4.56 min.

Example 13 (E)-2-(2,3-dichlorobenzylidene)hydrazinecarboximidamide acetate (BC2-7-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.54 (s, 1H), 8.16-8.04 (m, 1H), 7.64-7.52 (m, 1H), 7.40-7.23 (m, 1H), 1.93 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 178.84, 156.82, 142.89, 133.50, 133.07, 131.77, 131.44, 127.54, 125.55, 22.42. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 231.0199 Found 231.0195. HPLC 97.70% purity t_(R)=5.30 min.

Example 14 (E)-2-(3-chlorobenzylidene)hydrazinecarboximidamide acetate (BC2-9-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.15 (s, 1H), 7.95 (s, 1H), 7.71 (s, 1H), 7.47 (s, 2H), 2.01 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.30, 156.48, 145.64, 135.80, 134.52, 129.92, 129.89, 126.36, 125.82, 22.69. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 197.0589 Found 197.0602. HPLC 97.92% purity t_(R)=4.92 min.

Example 15 (E)-2-(2-fluorobenzylidene)hydrazinecarboximidamide acetate (BC2-11-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.35 (s, 1H), 8.08 (t, J=7.5 Hz, 1H), 7.44 (dd, J=13.8, 7.2 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.15 (t, 1H), 1.93 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.22, 162.25, 160.58, 156.46, 140.06, 140.03, 132.03, 131.97, 126.65, 126.64, 124.31, 124.29, 121.34, 121.27, 115.45, 115.31, 48.00, 47.86, 47.72, 47.58, 47.44, 47.29, 47.15, 22.61. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 181.0884 Found 181.0898. HPLC 98.05% purity t_(R)=2.28 min.

Example 16 (E)-2-(4-chlorobenzylidene)hydrazinecarboximidamide acetate (BC2-13-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.09 (s, 1H), 7.75 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 1.94 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.34, 156.38, 145.89, 135.93, 132.49, 128.60, 128.51, 22.72. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 197.0589 Found 197.0599. HPLC 96.79% purity t_(R)=4.96 min.

Example 17 (E)-2-(2-chloro-4-fluorobenzylidene)hydrazinecarboximidamide acetate (BC2-17-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.47 (s, 1H), 8.29-8.08 (m, 1H), 7.34-7.23 (m, 1H), 7.14 (s, 1H), 1.93 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.15, 164.38, 162.70, 156.55, 142.19, 134.88, 134.81, 129.01, 128.95, 127.76, 127.74, 116.65, 116.47, 114.67, 114.53, 22.59. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 215.0494 Found 215.0495. HPLC 95.95% purity t_(R)=4.95 min.

Example 18 (E)-2-(4-chloro-2-fluorobenzylidene)hydrazinecarboximidamide acetate (BC2-19-1)

White powder. ¹H NMR (600 MHz, cd3od) δ 8.52 (s, 1H), 8.33 (t, J=8.1 Hz, 1H), 7.58-7.41 (m, 2H), 2.17 (s, 3H). 13C NMR (151 MHz, cd3od) δ 179.05, 161.85, 160.16, 156.66, 138.85, 138.82, 136.71, 136.64, 127.68, 127.66, 124.88, 124.86, 120.49, 120.42, 116.20, 116.04, 22.50. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 215.0494 Found 215.0513. HPLC 95.29% purity t_(R)=5.06 min.

Example 19 (E)-2-(2-chloro-6-methoxybenzylidene)hydrazinecarboximidamide acetate (BC2-25-1)

Pale yellow powder. ¹H NMR (600 MHz, cd3od) δ 8.49 (s, 1H), 7.47 (t, J=8.3 Hz, 1H), 7.20 (d, J=12.0 Hz, 1H), 7.16 (d, J=6.0 Hz, 1H), 4.01 (s, 3H), 2.04 (s, 3H). ³C NMR (151 MHz, cd₃od) δ 178.39, 159.60, 156.36, 142.61, 133.60, 131.11, 122.35, 120.01, 109.76, 55.40, 22.26. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 227.0694 Found 227.0699. HPLC 95.71% purity t_(R)=4.59 min.

Example 20 (E)-2-(2,6-dimethylbenzylidene)hydrazinecarboximidamide acetate (BC2-27-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.54 (s, 1H), 7.23 (t, J=7.1 Hz, 1H), 7.14 (d, J=7.3 Hz, 2H), 2.51 (s, 6H), 1.98 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 179.14, 156.33, 147.66, 137.59, 130.45, 129.05, 128.31, 22.67, 19.86. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 191.1291 Found 191.1297. HPLC 95.55% purity t_(R)=5.07 min.

Example 21 (E)-2-(2-bromo-6-chlorobenzylidene)hydrazinecarboximidamide acetate (BC2-35-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.29 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.25 (t, J=8.0 Hz, 1H), 1.95 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 178.67, 156.49, 143.53, 134.57, 132.08, 131.11, 131.05, 129.38, 123.64, 22.45. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 274.9694 Found 274.9697. HPLC 95.51% purity t_(R)=5.02 min.

Example 22 (E)-2-(2-chloro-6-(trifluoromethyl)benzylidene)hydrazinecarboximidamide acetate (BC2-45-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.51 (s, 1H), 8.00-7.79 (m, 2H), 7.79-7.63 (m, 1H), 2.05 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 178.70, 156.62, 141.74, 135.30, 133.47, 130.65, 130.54, 130.37, 130.16, 125.14, 125.10, 125.07, 125.03, 124.24, 122.43, 22.25. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 265.0462 Found 265.0457. HPLC 97.55% purity t_(R)=5.11 min.

Example 23 (E)-2-(2,6-dibromobenzylidene)hydrazinecarboximidamide acetate (BC2-47-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.23 (s, 1H), 7.67 (d, J=7.9 Hz, 2H), 7.18 (t, J=7.8 Hz, 1H), 1.94 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 178.80, 156.63, 145.29, 133.03, 132.53, 131.35, 123.43, 22.38. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 318.9188 Found 318.9181. HPLC 95.86% purity t_(R)=5.11 min.

Example 24 (E)-2-(2-chloro-6-nitrobenzylidene)hydrazinecarboximidamide acetate (BC2-57-1)

Yellow powder. ¹H NMR (600 MHz, cd3od) δ 8.54 (s, 1H), 7.94-7.90 (m, 2H), 7.75-7.72 (m, 1H), 2.11 (s, 3H). ¹³C NMR (151 MHz, cd3od) δ 179.33, 157.20, 149.60, 139.44, 135.00, 133.24, 130.78, 125.51, 122.33, 22.68. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 242.0439 Found 242.0450. HPLC 95.14% purity t_(R)=4.31 min.

Example 25 (E)-2-(2-chloro-6-hydroxybenzylidene)hydrazinecarboximidamide acetate (BC2-59-1)

White powder. ¹H NMR (600 MHz, cd₃od) δ 8.88 (s, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 2.10 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 177.68, 158.85, 156.91, 147.07, 134.26, 131.51, 120.47, 115.47, 115.40, 21.71. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 213.0538 Found 213.0545. HPLC 96.07% purity t_(R)=4.45 min.

Example 26 (E)-2-(2,6-dichlorobenzylidene)hydrazinecarboxamide hydrochloride (BC1-262-1)

The 2,6-dichlorobenzaldehyde (5 mmol, 875 mg) and hydrazinecarboxamide hydrochloride (5 mmol 558 mg) in EtOH (10 ml) were shaken at reflux for 12 hours. After cooling at room temperature, the final compound was recovered as a precipitate after filtration. The crude compound was recrystalized from water to give the title compound (1.04 g, 79%) as a white powder. ¹H NMR (600 MHz, cd₃od) δ 8.13 (s, 1H), 7.44 (d, J=8.1 Hz, 2H), 7.31 (t, J=8.1 Hz, 1H). ¹³C NMR (151 MHz, cd₃od) δ 158.44, 136.36, 134.45, 130.14, 129.96, 128.81. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 232.0039 Found 232.0049. HPLC 95.70% purity t_(R)=4.58 min.

Example 27 N-(3,5-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine (BC1-242-2)

Step 1. methyl hydrogen (3,5-dichlorophenyl)carbonimidodithioate

To a well stirred cold solution of 3,5-dichloroaniline (1.62 g, 10 mmol) in DMF (20 ml) were added aqueous NaOH (20M, 1 ml), CS₂ (0.75 ml, 12.5 mmol) and CH₃I (0.78 ml, 12.5 mmol) in sequence at intervals of 30 min and stirring was continued for 4 h. The reaction mixture was then separated between water and EA. The EA layer was washed with water two times, dried with Na₂SO₄, evaporated and the residue obtained was used in the next step without further purification.

Step 2. N-(3,5-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine (BC1-242-2)

A solution of methyl hydrogen (3,5-dichlorophenyl)carbonimidodithioate (5 mmol, 1.26 g) in DMF (5 ml) was added to a solution of 1,2-diaminoethane (1.34 ml, 20 mmol) in DMF (5 ml) with stirring at rt. The reaction mixture was maintained at 120° C. for 8 h. Then the mixture was cooled and added to ice cold water. The resulting solid was purified by silica gel chromatography using EtOAc/hexanes, to obtain the title compound (50% for two steps) as a light yellow powder. ¹H NMR (600 MHz, cdcl₃) δ 6.92 (s, 1H), 6.85 (s, 2H), 5.59 (s, 2H), 3.52 (s, 4H). ¹³C NMR (151 MHz, cdcl₃) δ 158.77, 151.62, 135.02, 121.69, 121.52, 42.44. ESI-HRMS Calc m/z (M+H)⁻ Calc m/z 230.0246 Found 230.0251. HPLC 96.70% purity t_(R)=4.55 min.

Example 28 1-(2,6-dichlorophenyl)guanidine (BC1-256-2)

2,6-dichloroaniline (810 mg, 5 mmol), cyanamide (1.05 g, 25 mmol) and conc. HCl (5 ml) were heated together at 100° C. for 2 h. The mixture was cooled to 20° C. and made strongly basic with 7.5N NaOH solution, and the mixture was extracted with DCM three times. Organic layer was combined then dried over Na₂SO₄, evaporated and the residue obtained was purified by silica gel chromatography using DCM/MeOH, to obtain the title compound as a white powder (426 mg, 43% yield). ¹H NMR (600 MHz, cd₃od) δ 7.31 (d, J=8.1 Hz, 2H), 6.95 (t, J=8.0 Hz, 1H). ¹³C NMR (151 MHz, cd₃od) δ 154.62, 142.75, 130.94, 128.03, 123.75. ESI-HRMS Calc m/z (M+H)⁻ Calc m/z 204.0090 Found 204.0096. HPLC 95.67% purity t_(R)=1.85 min.

Example 29 1-(2,6-dichlorophenethyl)guanidine (BC1-252-2)

A mixture of 2,6-dichlorophenethylamine (0.57 g, 3 mmol), S-methylisothiouronium sulfate (0.56 g, 3 mmol), EtOH (4 ml) and water (2 ml) was refluxed until the evolution of MeSH ceased. The mixture was cooled to 20° C. and made strongly basic with 1N NaOH solution, and the mixture was extracted with DCM three times. Organic layer was combined then dried over Na₂SO₄, evaporated and the residue was recrystallized with water to give the title compound as a white powder (45%). ¹H NMR (600 MHz, cd₃od) δ 7.27 (d, J=7.9 Hz, 2H), 7.12 (t, J=7.9 Hz, 1H), 3.34 (t, J=6.8 Hz, 2H), 3.15 (t, J=6.7 Hz, 2H). ¹³C NMR (151 MHz, cd₃od) δ 157.49, 135.49, 133.81, 128.78, 128.23, 39.25, 30.10. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 232.0403 Found 232.0410. HPLC 95.70% purity t_(R)=4.58 min.

Example 30 (E)-2-(1-(2,6-dichlorophenyl)ethylidene)hydrazinecarboximidamide (BC1-259-2)

1-(2,6-dichlorophenyl)ethanone (373 mg, 1.97 mmol) and aminoguanidine hydrochloride (218 mg, 1.97 mmol) were refluxed in 10 ml EtOH with 78 ul of concentrated H₂SO₄ for 3 h. The reaction mixture was neutralized with 1N NaOH to PH=13. The solvent was evaporated and the residue was purified by silica gel chromatography using DCM/MeOH/NH₃. H₂O, to obtain the title compound as a white powder (12% yield). ¹H NMR (600 MHz, cd₃od) δ 7.39 (d, J=7.9 Hz, 2H), 7.30 (t, J=8.0 Hz, 1H), 2.18 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 159.47, 147.37, 137.15, 132.11, 129.84, 127.75, 21.20. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 245.0355 Found 245.0359. HPLC 95.25% purity t_(R)=5.11 min.

Example 31 (E)-2-(2,6-diiodobenzylidene)hydrazinecarboximidamide (BC2-55-2)

Step 1. 2,6-diiodobenzaldehyde

A mixture of 2,6-dibromobenzaldehyde (792 mg, 3 mmol), CuI (6.86 g, 36 mmol) and KI (19.92 g, 120 mmol) were refluxed in 20 ml 1,3-Dimethyl-2-imidazolidinone overnight. After cooled to rt, the reaction mixture was filtered and the filtrate was portioned between water and Et₂O. The aqueous layer was extracted with Et₂O three times and then the combined organic phase was washed with brine and dried over Na₂SO₄, evaporated and the residue was purified by silica gel chromatography using hexane/EA, to obtain the title compound as a yellow powder (355 mg, 35%). ¹H NMR (600 MHz, cdcl₃) δ 9.77 (s, 1H), 8.00 (d, J=7.8 Hz, 2H), 6.85 (t, J=7.8 Hz, 1H). ¹³C NMR (151 MHz, cdcl₃) δ 195.58, 141.39, 135.28, 134.46, 97.38.

Step 2. (E)-2-(2,6-diiodobenzylidene)hydrazinecarboximidamide (BC2-55-2)

2,6-diiodobenzaldehyde (355 mg, 0.99 mmol) and aminoguanidine bicarbonate (135 mg, 0.99 mmol) in EtOH (2 ml)-H₂O (4 ml)-HOAc(0.1 ml) were shaken at reflux for 12 hours. After cooling at room temperature, the solvent was evaporated and the residue was purified by silica gel chromatography using DCM/MeOH/NH₃. H₂O, to obtain the title compound as a yellow powder (200 mg, 49%). ¹H NMR (600 MHz, cd₃od) δ 7.97-7.96 (m, 3H), 6.71-6.68 (m, 1H). ¹³C NMR (151 MHz, cd₃od) δ 149.06, 144.67, 140.07, 139.52, 130.30, 96.29. ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 414.8911 Found 414.8919. HPLC 96.13% purity t_(R)=5.19 min.

Example 32 (E)-2-(2-amino-6-chlorobenzylidene)hydrazinecarboximidamide (BC2-61-1) and (E)-2-(2-aminobenzylidene)hydrazinecarboximidamide (bc2-61-2)

To a stirred solution of (E)-2-(2-chloro-6-nitrobenzylidene)hydrazinecarboximidamide acetate (650 mg, 2.16 mol) in MeOH (10 ml) was added Pd-C (33 mg), the resulting mixture was stirred under H₂ at rt overnight. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography using DCM/MeOH/NH₃. H₂O, to obtain the (E)-2-(2-amino-6-chlorobenzylidene)hydrazinecarboximidamide as a white powder (150 mg, 33%) ¹H NMR (600 MHz, cd₃od) δ 8.78 (s, 1H), 6.94 (t, J=8.0 Hz, 1H), 6.67-6.63 (m, 2H), ¹³C NMR (151 MHz, cd₃od) δ 159.82, 148.70, 147.29, 134.86, 129.14, 116.91, 116.88, 114.13, ESI-HRMS Calc m/z (M+H)⁻ Calc m/z 212.0697 Found 212.0710 HPLC 98.75% purity t_(R)=4.54 min and (E)-2-(2-aminobenzylidene)hydrazinecarboximidamide as a white powder (120 mg, 32%) ¹H NMR (600 MHz, cd₃od) δ 8.26 (s, 1H), 7.19 (d, J=4.2 Hz, 1H), 7.10 (d, J=6.8 Hz, 1H), 6.81 (d, J=4.6 Hz, 1H), 6.72 (d, J=3.0 Hz, 1H), ¹³C NMR (151 MHz, cd₃od) δ 159.47, 150.94, 146.63, 131.58, 128.85, 118.17, 116.40, 115.45, ESI-HRMS Calc m/z (M+H)⁺ Calc m/z 178.1087 Found 178.1100. HPLC 99.04% purity t_(R)=2.29 min.

Example 33 (E)-2-(2-chloro-5-(trifluoromethyl)benzylidene)hydrazine-1-carboximidamide acetate (JM1-221-2)

White powder. ¹H NMR (dmso-d₆, 600 MHz) δ 8.46 (s, 1H), 8.28 (s, 1H), 7.62 (d, 1H, J=8.2 Hz), 7.56 (d, 1H, J=8.2 Hz), 6.50 (br s, 2H), 6.14 (br s, 2H), 1.87 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 174.12, 160.12, 138.40, 138.18, 136.01, 134.38, 131.20, 128.76, 128.54, 124.13, 123.90, 22.88. ESI-HRMS Calc m/z for C₉H₉CIF₃N₄ 265.0462 (M+H)⁺, found 265.0467. HPLC 99.8% purity t_(R)=6.37 min.

Example 34 (E)-2-(2-fluoro-6-(trifluoromethyl)benzylidene)hydrazine-1-carboximidamide acetate (JM1-223-2)

White powder. ¹H NMR (dmso-d₆, 600 MHz) δ 8.10 (s, 1H), 7.57 (d, 1H, J=7.6 Hz), 7.53 (t, 1H, J=8.8 Hz), 7.46 (q, 1H, J=7.0 Hz), 5.90 (br s, 4H), 1.87 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 173.90, 161.51, 160.69, 129.84, 134.88, 129.99, 128.08, 124.96, 122.75, 121.08, 22.42. ESI-HRMS Calc m/z for C₉H₉F₄N₄ 249.0758 (M+H)⁺, found 249.0761. HPLC 99.8% purity t_(R)=5.54 min.

Example 35 (E)-2-(1-(3-chlorophenyl)propylidene)hydrazine-1-carboximidamide (JM1-257-2)

¹H NMR (cd₃od, 600 MHz) δ 7.96 (s, 1H), 7.77 (d, 1H, J=7.0 Hz), 7.42 (t, 1H, d, J=8.8 Hz), 2.81 (q, 2H, J=7.6 Hz), 1.18 (t, 3H, J=7.6 Hz). ¹³C NMR (150 MHz, cd₃od) δ 156.03, 155.14, 137.98, 134.08, 130.72, 130.00, 126.83, 15.51, 10.94. ESI-HRMS Calc m/z for C₁₀H₁₄ClN₄225.0907 (M+H)⁺, found 25.0897. HPLC 99.68% purity t_(R)=6.24 min.

Example 36 N-(2,6-dimethylphenyl)-4,5-dihydro-1H-imidazol-2-amine (JM2-59-2)

A mixture of sodium hydroxide (171.5 mg, 4.28 mmol) and ethylene diamine (184 mg, 3.06 mmol) were dissolved in 10 mL of ethanol and stirred at room temperature until obtained clear solution. To this solution was added drop wise 1,3-dimethyl-2-thionitrosobenzene (500 mg, 3.06 mmol) in 2 mL ethanol and refluxed for 20 h. The resulting solution was allowed to room temperature and acidified to pH ˜2 by bubbling hydrogen chloride through it. The suspension was filtered, the residue well washed with ethanol and the filtrate evaporated to yield crude compound. The crude was purified on silica using methanol in dichloromethane to obtain final compound as white solid. Yield 500 mg (72%). ¹H NMR (cd₃od, 600 MHz) δ 7.22 (t, 1H, J=8.2 Hz), 7.45 (d, 2H, J=7.0 Hz), 3.79 (s, 4H), 2.22 (s, 6H). ¹³C NMR (150 MHz, cd₃od) δ 159.17, 136.71, 136.31, 128.77, 128.43, 39.25, 16.47. ESI-HRMS Calc m/z for C₁₁H₁₆N₃ 190.1339 (M+H)⁻, found 190.1342.

Example 37 (E)-2-(2,6-dichloro-4-methoxybenzylidene)hydrazine-1-carboximidamide (JM2-63-2)

Step 1. 2,6-dichloro-4-methoxybenzaldehyde

To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (140 mg, 0.73 mmol) in 4 mL DMF added 203 mg (1.465 mmol) of K₂CO₃ and stirred at room temperature for 3 h. The reaction mixture was extracted with water and ethyl acetate. The organic layer was washed with brine (X3), dried on Na2SO4. The solvent was evaporated to obtain crude compound as dark red color. The crude was purified on silica with hexane/ethyl acetate to obtain white solid (130 mg, 87%). ¹H NMR (dmso-d₆, 600 MHz) δ 10.35 (s, 1H), 6.85(s, 1H), 3.81(s, 3H).

Step 2. (E)-2-(2,6-dichloro-4-methoxybenzylidene)hydrazine-1-carboximidamide (JM2-63-2)

To a solution of 2,6-dichloro-4-methoxybenzaldehyde (90 mg, 0.44 mmol) in 2 mL ethanol was added aminoguanidine bicarbonate (60.3 mg, 0.44 mmol) and refluxed for overnight. The solvent was evaporated after allowing to room temperature and recrystallized from ethanol. Brown crystals (80 mg, 69%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.10 (s, 1H), 7.06 (s, 2H), 5.71 (s, 2H), 5.60 (s, 2H), 3.28 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 161.51, 158.63, 138.15, 134.40, 124.82, 115.56, 56.46. ESI-HRMS Calc m/z for C₉H₁₁Cl₂N₄O 261.0304 (M+H)⁺, found 261.0310. HPLC 99.72% purity t_(R)=6.10 min.

Example 38 (E)-2-(4-(benzyloxy)-2,6-dichlorobenzylidene)hydrazine-1-carboximidamide (JM2-67-2)

Step 1. 4-(benzyloxy)-2,6-dichlorobenzaldehyde

To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (200 mg, 1.04 mmol) in 8 mL DMF added 287 mg (2.08 mmol) of K₂CO₃ and stirred at room temperature for 1 h. The reaction mixture was extracted with water and ethyl acetate. The organic layer was washed with brine (X3), dried on Na₂SO₄. The solvent was evaporated to obtain crude compound as dark red color. The crude was purified on silica with hexane/ethyl acetate to obtain white solid (220 mg, 75%). ¹H NMR (dmso-d₆, 600 MHz) δ 10.25 (s, 1H), 7.42 (d, 2H, J=7.6 Hz), 7.38 (t, 2H, d, J=7.0 Hz), 7.34 (d, 1H, J=7.6 Hz), 7.28 (s, 2H), 5.24 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 168.01, 162.24, 138.03, 135.96, 128.99, 128.75, 128.44, 126.82, 122.89, 117.08, 70.08.

Step 2. (E)-2-(4-(benzyloxy)-2,6-dichlorobenzylidene)hydrazine-1-carboximidamide (JM2-67-2)

To a solution of 4-(benzyloxy)-2,6-dichlorobenzaldehyde (150 mg, 0.53 mmol) in 4 mL ethanol was added aminoguanidine bicarbonate (72.6 mg, 0.53 mmol) and refluxed for overnight. The solvent was evaporated after allowing to room temperature and recrystallized from ethanol. Off-white needles: ¹H NMR (dmso-d₆, 600 MHz) δ 8.09 (s, 1H), 7.41 (d, 2H, J=7.0 Hz), 7.37 (t, 2H, d, J=7.0 Hz), 7.31 (t, 1H, J=7.0 Hz), 7.15 (s, 2H), 5.71 (s, 2H), 5.61 (s, 2H), 5.15 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 161.52, 157.64, 138.10, 136.58, 134.37, 128.93, 128.53, 128.26, 125.07, 116.40, 70.38. ESI-HRMS Calc m/z for C₁₅H₁₅Cl₂N4O 337.0617 (M+H)⁺, found 337.0612. HPLC 99.64% purity t_(R)=8.02 min.

Example 39 (E)-2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-83-2)

¹H NMR (dmso-d₆, 600 MHz) δ 12.60 (s, 1H), 8.59 (br s, 2H), 8.38 (s, 1H), 7.56 (d, 2H, J=8.2 Hz), 7.45 (t, 1H, J=8.2 Hz), 3.68 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.10, 144.69, 134.47, 132.25, 129.47, 43.31. ESI-HRMS Calc m/z for C₁₀H₁₁Cl₂N₄ 257.0355 (M+H)⁺, found 257.0349. HPLC 99.37% purity t_(R)=6.44 min.

Example 40 (E)-2-(2-(2,6-dimethylbenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-85-2)

¹H NMR (dmso-d₆, 600 MHz) δ 12.27 (s, 1H), 8.49 (s, 1H), 8.45 (br s, 2H), 7.18 (t, 1H, J=7.6 Hz), 7.08 (d, 2H, J=7.6 Hz), 3.68 (s, 4H), 2.37 (s, 6H). ¹³C NMR (150 MHz, dmso-d₆) δ158.03, 149.34, 137.92, 130.66, 129.81, 128.26, 43.25, 21.25. ESI-HRMS Calc m/z for C₁₂H₁₇N₄ 217.1448 (M+H)⁺, found 217.1440. HPLC 98.73% purity t_(R)=5.72 min.

Example 41 2-(2,6-dichlorobenzyl)-4,5-dihydro-1H-imidazole (JM2-87-2)

The mixture of 2-(2,6-dichlorophenyl)acetonitrile (200 mg, 1.07 mmol), ethylene diamine (484 mg, 8.06 mmol) and Sulfur (17.5 mg, 0.54 mmol) heated at 200° C. for 20 min at microwave. After allowing to room temperature added cold water and extracted with ether to yield crude product. The crude was purified on silica column using methanol in dichloromethane as eluent. The final product was obtained as off-white solid (67%). ¹H NMR (dmso-d₆, 600 MHz) δ 7.40 (d, 2H, J=8.2 Hz), 7.25 (t, 1H, J=8.2 Hz), 6.32 (br s, 2H), 3.66 (s, 2H), 3.31 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 163.73, 135.68, 133.89, 129.37, 128.45, 31.31. ESI-HRMS Calc m/z for C₁₀H₁₁Cl₂N₂ 229.0294 (M+H)⁺, found 229.0301. HPLC 96%.

Example 42 (E)-2-(2-(2-chloro-6-nitrobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-89-2)

¹H NMR (dmso-d₆, 600 MHz) δ 12.81 (s, 1H), 8.59 (br s, 2H), 8.47 (s, 1H), 8.06 (d, 1H, J=7.0 Hz), 7.95 (d, 1H, J=7.6 Hz), 7.71 (t, 1H, J=8.2 Hz), 3.65 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.10, 149.76, 143.82, 135.01, 132.32, 126.84, 124.02, 43.28. ESI-HRMS Calc m/z for C₁₀H₁₁ClN₅O₂ 268.0596(M+H)⁻, found 268.0587. HPLC 98.25% purity t_(R)=6.77 min.

Example 43 (E)-2-(2-(3,4-dichlorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-91-2)

¹H NMR (dmso-d₆, 600 MHz) δ 12.43 (s, 1H), 8.18 (s, 1H), 8.12 (s, 1H), 7.76 (d, 1H, J=8.2 Hz), 7.71 (d, 1H, J=8.2 Hz), 3.72 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.30, 145.85, 134.52, 133.26, 132.25, 131.42, 128.96, 128.34, 43.33. ESI-HRMS Calc m/z for C₁₀H₁₁Cl₂N₄ 257.0355 (M+H)⁺, found 257.0343. HPLC 98.38% purity t_(R)=7.03 min.

Example 44 (E)-2-(2-(2-chloro-6-fluorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-95-2)

¹H NMR (dmso-d₆, 600 MHz) δ 12.62 (s, 1H), 8.91 (br s, 2H), 8.49 (s, 1H), 8.08 (d, 1H, J=9.4 Hz), 7.58 (t, 1H, J=7.0 Hz), 7.35 (t, 1H, J=7.6 Hz), 3.74 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 162.22, 160.60, 158.14, 143.19, 133.00, 132.28, 129.04, 119.72, 114.02, 43.15. ESI-HRMS Calc m/z for C₁₀H₁₁ClFN₄ 241.0651 (M+H)⁺, found 241.0662. HPLC 99.75% purity t_(R)=6.21 min.

Example 45 N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine hydrochloride (JM2-97-2)

A mixture of sodium hydroxide (171.5 mg, 4.28 mmol) and ethylene diamine (184 mg, 3.06 mmol) were dissolved in 10 mL of ethanol and stirred at room temperature until obtained clear solution. To this solution was added drop wise 1,3-dichloro-2-thionitrosobenzene (500 mg, 3.06 mmol) in 2 mL ethanol and refluxed for 20 h. The resulting solution was allowed to room temperature and acidified to pH ˜2 by bubbling hydrogen chloride through it. The suspension was filtered, the residue well washed with ethanol and the filtrate evaporated to yield crude compound. The crude was purified on silica using methanol in dichloromethane to obtain final compound as white solid. Yield 470 mg (72%). ¹H NMR (dmso-d₆, 600 MHz) δ 10.67 (s, 1H), 8.49 (br s, 2H), 7.61 (d, 2H, J=7.6 Hz), 7.45 (t, 1H, J=7.6 Hz), 3.29 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.43, 134.49, 131.30, 129.64, 109.99, 43.15. ESI-HRMS Calc m/z for C₉H₁₀Cl₂N₃ 230.0246 (M+H)⁺, found 230.0254. HPLC 99.54% purity t_(R)=3.72 min.

Example 46 2-(1-(2,6-dichlorophenyl)ethyl)-4,5-dihydro-1H-imidazole (JM2-101-2)

Step 1. 2-(2,6-dichlorophenyl)propanenitrile

1,3-dichloro-2-(chloromethyl)benzene (500 mg, 2.7 mmol) was dissolved in THF (6 mL) under Argon. The mixture was cooled to −70° C. then added KO^(t)Bu (303 mg, 2.7 mg) followed by methyl iodide (381 mg, 2.7 mmol) under argon. The reaction was stirred at −70° C. for 1 h then was allowed to warm to room temperature and stirring continued for 12 h. The solution was concentrated in vacuo to remove THF and extracted with ethyl acetate and 1 M HCl followed by washing with sat. NaHCO₃ solution, brine, was dried over Na₂SO₄, and concentrated. The residue was purified by silica gel chromatography using 10% ethyl acetate in hexanes. The final product obtained as a yellow color oil. Yield 480 mg (89%). ¹H NMR (cdcl₃, 600 MHz) δ 7.34 (d, 2H, J=8.2 Hz), 7.20 (t, 1H, J=8.2 Hz), 4.82 (q, 1H, J=7.0 Hz), 1.68 (d, 3H, J=7.0 Hz). ESI-MS (M+H)⁺ 200.01.

Step 2. 2-(1-(2,6-dichlorophenyl)ethyl)-4,5-dihydro-1H-imidazole (JM2-101-2)

The mixture of 2-(2,6-dichlorophenyl)propanenitrile (200 mg, 1.0 mmol), ethylene diamine (450 mg, 7.5 mmol) and Sulfur (16 mg, 0.5 mmol) heated at 200° C. for 25 min in microwave. After allowing to room temperature added cold water and extracted with ether to yield crude product. The crude was purified on silica column using methanol in dichloromethane as eluent. The final product was obtained as off-white solid (42%). ¹HNMR (cdcl₃, 600 MHz) δ7.34 (d, 2H, J=8.2 Hz), 7.20 (t, 1H, J=8.2 Hz), 4.82 (q, 1H, J=7.0 Hz), 3.41 (s, 4H), 1.68 (d, 3H, J=7.0 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 167.60, 138.22, 135.14, 129.51, 129.44, 36.70, 15.48. ESI-HRMS Calc m/z for C₁₁H₁₃Cl₂N₂ 243.0450 (M+H)⁺, found 243.0443.

Example 47 (E)-2-(2-(2,6-difluorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-103-2)

¹H NMR (dmso-d₆, 600 MHz) δ 12.47 (s, 1H), 8.54 (br s, 2H), 8.31 (s, 1H), 7.53 (t, 1H, J=7.0 Hz), 7.20 (t, 2H, J=8.2 Hz), 3.69 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 161.51, 159.86, 157.89, 139.55, 133.17, 112.74, 110.91, 43.33. ESI-HRMS Calc m/z for C₁₀H₁₁F₂N₄ 225.0946 (M+H)⁺, found 225.0955. HPLC 99.57% purity t_(R)=4.66 min.

Example 48 (E)-2-(2-(2-bromo-6-nitrobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-109-2)

Yellow powder. ¹H NMR (dmso-d₆, 600 MHz) δ 12.77 (s, 1H), 8.61 (br s, 2H), 8.43 (s, 1H), 8.09 (t, 2H, J=7.6 Hz), 7.63 (t, 1H, J=7.6 Hz), 3.65 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.03, 149.84, 145.46, 138.00, 132.58, 128.37, 124.55, 124.47, 43.28. ESI-HRMS Calc m/z for C₁₀H₁₁BrN₅O₂ 312.0091 (M+H)⁺, found 312.0082. HPLC 96.81% purity t_(R)=6.65 min.

Example 49 (E)-2-(2-(2,6-dibromobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-111-2)

Cream color powder. ¹H NMR (dmso-d₆, 600 MHz) δ 12.58 (s, 1H), 8.63 (br s, 2H), 8.25 (s, 1H), 7.75 (d, 2H, J=7.6 Hz), 7.29 (t, 1H, J=7.6 Hz), 3.68 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.08, 147.92, 135.51, 132.94, 132.89, 123.81, 43.31. ESI-HRMS Calc m/z for C₁₀H₁₁Br₂N₄ 344.9345 (M+H)⁺, found 344.9357. HPLC 97.29% purity t_(R)=6.73 min.

Example 50 (E)-2-(2-(2-chlorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-113-2)

Yellow color powder. ¹H NMR (dmso-d₆, 600 MHz) δ 12.51 (s, 1H), 8.79 (br s, 2H), 8.55 (s, 1H), 8.18 (d, 1H, J=7.6 Hz), 7.51 (d, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.0 Hz), 7.41 (t, 1H, J=7.6 Hz), 3.73 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.13, 144.43, 133.81, 132.58, 130.91, 130.38, 127.93, 127.82, 43.32. ESI-HRMS Calc m/z for C₁₀H₁₂ClN₄ 223.0745 (M+H)⁻, found 223.0736. HPLC 98.73% purity t_(R)=5.52 min.

Example 51 (E)-2-(2-(2-fluorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-115-2)

Purple color powder. ¹H NMR (dmso-d₆, 600 MHz) δ 12.23 (s, 1H), 8.75 (br s, 2H), 8.36 (s, 1H), 8.10 (t, 1H, J=7.0 Hz), 7.79 (q, 1H, J=6.4 Hz), 7.28 (t, 2H, J=8.2 Hz), 3.72 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.17, 141.28, 133.23, 133.17, 127.19, 125.25, 116.55, 116.42, 43.24. ESI-HRMS Calc m/z for C₁₀H₁₂FN₄ 207.1041 (M+H)⁺, found 207.1030. HPLC 98.15% purity t_(R)=4.91 min.

Example 52 (E)-2-(2-(2-chloro-6-(trifluoromethyl)benzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-131-2)

White solid. ¹H NMR (dmso-d₆, 600 MHz) δ 12.80 (s, 1H), 8.73 (br s, 3H), 7.54 (d, 1H, J=8.2 Hz), 7.50 (t, 1H, J=7.6 Hz), 7.46 (d, 1H, J=7.6 Hz), 3.87 (s, 4H), 2.65 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.04, 147.26, 140.30, 134.42, 131.21, 130.59, 129.79, 127.72, 43.27, 22.07. ESI-HRMS Calc m/z for C₁₁H₁₁ClF₃N₄ 291.0619 (M+H)⁺, found 291.0608.

Example 53 (E)-2-(2-(2-fluoro-6-methylbenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-133-2)

Yellow powder. ¹H NMR (dmso-d₆, 600 MHz) δ 12.42 (s, 1H), 8.53 (br s, 2H), 8.51 (s, 1H), 7.37 (d, 1H, J=7.6 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.27 (d, 1H, J=7.0 Hz), 3.70 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.06, 147.22, 140.29, 134.41, 131.20, 130.58, 129.82, 127.72, 43.28, 22.07. ESI-HRMS Calc m/z for C₁₁H₁₄ClN₄ 279.0619 (M+H)⁺, found 276.0629.

Example 54 (E)-2-(2-(2-bromobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM2-191-2)

Yellow powder. ¹H NMR (dmso-d₆, 600 MHz) δ 12.63 (s, 1H), 8.92 (br s, 2H), 8.61 (s, 1H), 8.27 (d, 1H, J=8.2 Hz), 7.79 (d, 1H, J=8.2 Hz), 7.56 (t, 1H, J=7.6 Hz), 7.48 (t, 1H, J=8.2 Hz), 3.83 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 160.31, 148.98, 135.80, 134.99, 134.58, 130.59, 130.38, 126.38. ESI-HRMS Calc m/z for C₁₀H₁₂BrN₄ 267.0240 (M+H)⁻, found 267.0252.

Example 55 (Z)-2-(2,6-dichlorobenzylidene)hydrazinecarboximidamide acetate (BC1-55-1)

White powder. ¹H NMR (600 MHz, CD3OD) δ 7.67(s, 1H), 7.54(d, 2H, J=6.0 Hz), 7.50(t, 1H, J=6.0 Hz), 1.84(s, 3H). ¹³C NMR (150 MHz, CD3OD) δ 178.8, 156.7, 140.2, 133.5, 132.2, 129.0, 128.4, 22.6. ESI-HRMS Calc m/z for C₈H₉Cl₂N₄ 231.0199 (M+H)⁺, found 231.0198.

Example 56 (Z)-2-(2,6-dichloro-4-hydroxybenzylidene)hydrazinecarboximidamide acetate (BC1-167-1)

Light yellow solid. ¹H NMR (600 MHz, cd₃od) δ 8.31 (s, 1H), 6.84 (s, 2H), 1.92 (s, 3H). ¹³C NMR (151 MHz, cd₃od) δ 177.83, 160.34, 156.27, 143.19, 135.41, 119.44, 116.43, 53.13, 47.99, 47.85, 47.71, 47.56, 47.42, 47.28, 47.14, 21.89. ESI-HRMS Calc m/z for C₈H₉Cl₂N₄O 247.0148 (M+H)⁻, found 247.0149.

Example 57 1-(2-(2,6-dichlorophenyl)-1H-imidazol-1-yl)guanidine (BC1-267-2)

¹H NMR (600 MHz, cd₃od) δ 7.49-7.43 (m, 3H), 7.20 (s, 1H), 7.17 (s, 1H). ¹³C NMR (151 MHz, cd₃od) δ 161.67, 140.40, 136.96, 131.34, 129.08, 127.59, 125.5, 120.01. ESI-HRMS Calc m/z for C₁₀H₁₀Cl₂N₅ 270.0313 (M+H)⁺, found 270.0314.

Example 58 (E)-2-(2,6-dichlorobenzylidene)-N-methylhydrazine-1-carboximidamide hydroiodide (JM2-171-2)

Yellow solid. ¹H NMR (dmso-d₆, 600 MHz) δ 11.79 (s, 1H), 8.38 (s, 1H), 7.90 (br s, 1H), 7.84 (br s, 2H), 7.57 (d, 2H, J=8.2 Hz), 7.46 (t, 1H, J=8.2 Hz), 2.84 (d, 3H, J=4.1 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 155.51, 134.45, 133.47, 131.95, 130.51, 129.48, 28.62. ESI-MS (M+H)⁺ 245.03.

Example 59 (E)-2-(2,6-dichlorobenzylidene)-N,N-dimethylhydrazine-1-carboximidamide hydroiodide (JM2-289-2)

White solid. ¹H NMR (dmso-d₆, 600 MHz) δ 11.55 (s, 1H), 8.53 (s, 1H), 7.63 (br s, 2H), 7.57 (d, 2H, J=7.6 Hz), 7.45 (t, 1H, J=8.2 Hz), 3.07 (s, 6H). ¹³C NMR (150 MHz, dmso-d₆) δ 156.69, 134.74, 134.16, 130.92, 130.61, 129.69, 40.52. ESI-MS (M+H)⁺ 259.05. ESI-HRMS Calc m/z for C₁₀H₁₃Cl₂N₄ 259.0512 (M+H)⁻, found 259.0519. HPLC 95.24% purity t_(R)=8.55 min.

Example 60 (E)-2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-1,4,5,6-tetrahydropyrimidine hydrochloride (JM2-255-2)

White solid (40%). ¹H NMR (dmso-d₆, 600 MHz) δ 12.57 (s, 1H), 8.38 (s, 1H), 8.33 (br s, 2H), 7.55 (d, 2H, J=8.2 Hz), 7.45 (t, 1H, J=8.2 Hz), 3.32 (m, 4H), 1.86 (t, 2H, J=5.2 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 151.46, 141.87, 134.48, 132.00, 130.56, 129.39, 38.55, 19.83. ESI-HRMS Calc m/z for C₁₁H₁₃Cl₂N₄ 271.0512 (M+H)⁺, found 271.0524. HPLC 98.82% purity t_(R)=7.80 min.

Example 61 (E)-2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-1,4,5,6-tetrahydropyrimidine hydrochloride (JM2-257-2)

White solid (45%). ¹H NMR (dmso-d₆, 600 MHz) δ 11.99 (s, 1H), 8.47 (s, 1H), 8.20 (br s, 2H), 7.17 (t, 1H, J=7.6 Hz), 7.08 (d, 2H, J=7.6 Hz), 3.32 (m, 4H), 2.37 (s, 6H), 1.87 (t, 2H, J=4.1 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 151.48, 146.83, 137.68, 131.22, 129.51, 128.84, 38.55, 21.15, 20.02. ESI-HRMS Calc m/z for C₁₃H₁₉N₄ 231.1604 (M+H)⁺, found 231.1609. HPLC 98.92% purity t_(R)=8.07 min.

Example 62 (E)-2-(2-(2-chloro-6-nitrobenzylidene)hydrazinyl)-1,4,5,6-tetrahydropyrimidine hydrochloride (JM2-263-2)

Yellow solid (37%). ¹H NMR (dmso-d₆, 600 MHz) δ 12.29 (s, 1H), 8.48 (s, 1H), 8.27 (br s, 2H), 7.36 (d, 1H, J=7.6 Hz), 7.32 (t, 1H, J=7.6 Hz), 7.27 (t, 1H, J=7.6 Hz), 3.33 (m, 4H), 1.87 (t, 2H, J=4.7 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 151.33, 149.87, 140.80, 134.87, 132.09, 127.15, 123.97, 38.46, 19.74. ESI-HRMS Calc m/z for C₁₁H₁₃ClN₅O₂ 282.0752 (M+H)⁺, found 282.0746. HPLC 96.41% purity t_(R)=7.14 min.

Example 63 (E)-2-(2-(2-chloro-6-methylbenzylidene)hydrazinyl)-1,4,5,6-tetrahydropyrimidine hydrochloride (JM2-265-2)

Yellow solid (44%). ¹H NMR (dmso-d₆, 600 MHz) δ 12.60 (s, 1H), 8.47 (s, 1H), 8.33 (br s, 2H), 8.06 (d, 1H, J=8.2 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.71 (t, 1H, J=8.2 Hz), 3.29 (m, 4H), 2.48 (s, 3H), 1.84 (t, 2H, J=4.7 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 153.64, 146.77, 142.33, 136.39, 133.09, 132.62, 132.54, 129.80, 40.73, 24.09, 22.09. ESI-HRMS Calc m/z for C₁₂H₁₆ClN₄ 251.1058 (M+H)⁺, found 251.1064. HPLC 98.55% purity t_(R)=7.82 min.

Example 64 2-(2,6-dichlorobenzyl)-1,4,5,6-tetrahydropyrimidine (JM2-271-2)

2-(2,6-dichlorophenyl)acetonitrile (100 mg, 0.54 mmol) and propane-1,3-diamine (298 mg, 4.0 mmol) was taken in a reaction vial and added sulfur (8.5 mg, 0.29 mmol). The reaction mixture was heated at 100° C. for overnight. After allowing to room temp added cold water and extracted with ether to yield crude product. The crude was purified on silica column using methanol in dichloromethane as eluent. The final product was obtained as dark brown solid (42%). ¹H NMR (dmso-d₆, 600 MHz) δ 7.37 (d, 2H, J=8.2 Hz), 7.23 (t, 1H, J=8.2 Hz), 3.59 (s, 2H), 3.07 (t, 4H, J=5.2 Hz), 1.56-1.53 (m, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 153.38, 136.01, 134.31, 129.06, 128.32, 37.00, 20.89, 15.62. ESI-HRMS Calc m/z for C₁₁H₁₃Cl₂N₂ 243.0450 (M+H)⁺, found 243.0456. HPLC 95.36% purity t_(R)=7.41 min.

Example 65 N-carbamimidoyl-2-(2-chloro-6-nitrophenyl)acetamide hydrochloride (JM2-275-2)

A solution of methyl 2-(2-chloro-6-nitrophenyl)acetate (80 mg, 0.35 mmol) in ethanol (3 mL) was added to a solution of guanidine hydrochloride (34 mg, 0.35 mmol) and sodium ethoxide (8.1 mg of sodium in 2 mL methanol). The resulting solution was stirred at room temp for 16 h. The reaction mixture was evaporated and extracted with chloroform/water. The organic layer was mixed with ethanolic solution to get product as hydrochloric salt. White Solid (35 mg, 34%). ¹H NMR (dmso-d₆, 600 MHz) δ 12.74 (s, 1H), 8.00 (d, 1H, J=8.2 Hz), 7.89 (d, 1H, J=7.6 Hz), 7.58 (t, 1H, J=8.2 Hz), 3.99 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 170.39, 151.03, 136.50, 134.66, 129.86, 128.51, 124.11, 35.80. ESI-HRMS Calc m/z for C₉H₁₀ClN₄O₃ 257.0436 (M+H)⁺, found 257.0449. HPLC 97.60% purity t_(R)=19.16 min.

Example 66 (E)-2-(thiophen-2-ylmethylene)hydrazine-1-carboximidamide (JM2-279-2)

Yellow crystals (75%). ¹H NMR (dmso-d₆, 600 MHz) δ 7.54 (s, 1H), 7.47 (d, 1H, J=4.7 Hz), 7.26 (d, 1H, J=3.52 Hz), 7.00 (t, 1H, J=3.52 Hz), 5.89 (br s, 2H), 5.51 (br s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 160.41, 136.23, 135.51, 129.81, 128.58, 125.85. ESI-HRMS Calc m/z for C₆H₉N₄S 169.0542 (M+H)⁻, found 169.0560. HPLC 98.56% purity t_(R)=7.96 min.

Example 67 N-carbamimidoyl-2-(2,6-dichlorophenyl)acetamide hydrochloride (JM2-287-2)

A solution of methyl 2-(2,6-dichlorophenyl)acetate (75 mg, 0.26 mmol) in ethanol (3 mL) was added to a solution of guanidine hydrochloride (25 mg, 0.26 mmol) and sodium ethoxide (6.0 mg of sodium in 2 mL methanol). The resulting solution was stirred at room temp for 30 h. The reaction mixture was evaporated and extracted with chloroform/water. The organic layer was mixed with ethanolic solution to get product as hydrochloric salt. White Solid (15 mg, 15%). ¹H NMR (dmso-d₆, 600 MHz) δ 12.18 (s, 1H), 8.40 (br s, 2H), 8.18 (br s, 2H), 7.51 (d, 2H, J=8.2 Hz), 7.38 (t, 1H, J=7.6 Hz), 4.13 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 170.91, 154.88, 135.92, 130.67, 130.58, 128.74, 39.34. ESI-HRMS Calc m/z for C₉H₁₀Cl₂N₃O 246.0195 (M+H)⁺, found 246.0200. HPLC 96.56% purity t_(R)=19.17 min.

Example 68 (E)-2-(2,5-dichlorobenzylidene)hydrazine-1-carboximidamide acetate (JM3-11-2)

White solid. ¹H NMR (dmso-d₆, 600 MHz) δ 8.29 (s, 1H), 8.25 (s, 1H), 7.43 (d, 1H, J=8.2 Hz), 7.34 (t, 1H, J=8.2 Hz), 7.06 (br s, 4H), 1.82 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 174.86, 159.62, 138.38, 134.98, 132.68, 131.67, 130.87, 129.76, 126.57, 23.15. ESI-HRMS Calc m/z for C₈H₉Cl₂N₄ 231.0199 (M+H)⁺, found 231.0202. HPLC 99.64% purity t_(R)=7.95 min.

Example 69 (E)-2-(2-nitrobenzylidene)hydrazine-1-carboximidamide acetate (JM3-13-2)

Light yellow powder. ¹H NMR (dmso-d₆, 600 MHz) δ 8.30 (s, 1H), 8.29 (s, 1H), 7.92 (d, 1H, J=8.2 Hz), 7.66 (t, 1H, J=7.6 Hz), 7.50 (t, 1H, J=7.6 Hz), 6.90 (br s, 4H), 1.83 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 174.57, 160.21, 147.99, 138.68, 133.28, 130.22, 129.31, 128.45, 124.67, 22.94. ESI-HRMS Calc m/z for C₈H₁₀N₅O₂ 208.0829 (M+H)⁺, found 208.0839. HPLC 97.52% purity t_(R)=5.16 min.

Example 70 (E)-2-(2-hydroxybenzylidene)hydrazine-1-carboximidamide acetate (JM3-17-2)

Light orange powder. ¹H NMR (dmso-d₆, 600 MHz) δ 11.24 (br s, 1H), 8.22 (s, 1H), 7.43 (d, 1H, J=7.6 Hz), 7.16 (t, 1H, J=7.0 Hz), 6.84 (t, 2H, J=8.8 Hz), 6.04 (br s, 4H), 1.88 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 175.39, 157.94, 157.08, 144.66, 30.73, 128.18, 120.67, 119.45, 116.32, 23.71. ESI-HRMS Calc m/z for C₈H₁₁N₄O 179.0927 (M+H)⁺, found 179.0932. HPLC 98.13% purity t_(R)=4.84 min.

Example 71 1-(2-(2,6-dichlorophenyl)-2-hydroxyethyl)guanidine (JM3-27-2)

A mixture of 2-amino-1-(2,6-dichlorophenyl)ethan-1-ol (50 mg, 0.24 mmol), S-methylisothiouronium sulfate (33 mg, 0. 12 mmol), EtOH (2 ml) and water (1 ml) was refluxed until the evolution of MeSH ceased. The mixture was allowed to room temp and made strongly basic with 1N NaOH solution, and the mixture was extracted with dichloromethane (3X). Organic layer was combined then dried over Na₂SO₄, evaporated and the residue was recrystallized with ethanol/water to give the title compound as a white powder (50%). ¹H NMR (dmso-d₆+3 drops of cd₃od, 400 MHz) δ 7.45 (d, 2H, J=7.5 Hz), 7.34 (t, 1H, J=7.5 Hz), 5.42 (dd, 1H, J=4.4 Hz), 3.70 (dd, 1H, J=4.6 Hz), 3.38 (dd, 1H, J=4.6 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 158.07, 136.36, 134.77, 130.41, 129.96, 69.13, 44.90. ESI-HRMS Calc m/z for C₉H₁₂Cl₂N₃O 248.0352 (M+H)⁺, found 248.0354. HPLC 96.25% purity t_(R)=1.99 min.

Example 72 (E)-2-((2,4-dichloropyridin-3-yl)methylene)hydrazine-1-carboximidamide acetate (JM3-29-2)

White powder. ¹H NMR (dmso-d₆, 600 MHz) δ 8.20 (d, 1H, J=4.7 Hz), 8.14 (s, 1H), 7.59 (d, 1H, J=5.2 Hz), 5.96 (s, 4H), 1.89 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 173.03, 161.69, 150.35, 147.80, 143.29, 136.34, 128.89, 125.75, 21.90. ESI-HRMS Calc m/z for C₇H₈Cl₂N₅ 232.0151 (M+H)⁺, found 232.0157. HPLC 99.30% purity t_(R)=4.95 min.

Example 73 (E)-2-(4-bromo-2-chlorobenzylidene)hydrazine-1-carboximidamide acetate (JM3-57-2)

Off-white powder. ¹H NMR (dmso-d₆, 600 MHz) δ 8.22 (s, 1H), 8.11 (d, 1H, J=8.2 Hz), 7.68 (s, 1H), 7.47 (d, 1H, J=8.2 Hz), 6.52 (br s, 4H), 1.85 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 173.80, 160.73, 138.23, 133.19, 132.91, 132.09, 130.58, 128.74, 121.60, 22.48. ESI-HRMS Calc m/z for C₁₄H₁₄ClN₄ 273.0902 (M+H)⁺, found 273.0899. HPLC 99.83% purity t_(R)=9.29 min.

Example 74 (E)-2-((3-chloro-└1,1′-biphenyl┘-4-yl)methylene)hydrazine-1-carboximidamide acetate (JM3-63-2)

The mixture of compound (E)-2-(4-bromo-2-chlorobenzylidene)hydrazine-1-carboximidamide (90 mg, 0.33 mmol), phenyl boronic acid (52 mg, 0.42 mmol), Pd(PPh₃)₄ (19 mg, 0.06 mmol), and K₂CO₃ (112 mg, 0.82 mmol)) in dimethoxyethane/H₂O (4:1) was irradiated at 150° C. for 30 min under microwave conditions. The black residue formed was filtered through Celite and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography using methanol in dichloromethane as eluent to yield solid. The solid was dissolved in diethyl ether (5 mL) then added AcOH (1 equiv) to furnish final compound as off-white powder (68%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.38 (s, 1H), 8.27 (d, 1H, J=8.2 Hz), 7.73 (d, 3H, J=8.8 Hz), 7.63 (t, 1H, J=7.6 Hz), 7.47 (t, 2H, J=7.6 Hz), 7.39 (d, 1H, J=7.0 Hz), 6.71 (br s, 4H), 1.87 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 173.29, 159.47, 142.03, 140.09, 138.56, 133.21, 132.08, 129.53, 128.70, 127.98, 127.81, 127.16, 125.83, 22.08. ESI-HRMS Calc m/z for C₁₄H₁₄ClN₄ 273.0902 (M+H)⁺, found 273.0899. HPLC 96.54% purity t_(R)=11.51 min.

Example 75 (E)-2-((3,5-dichloro[1,1′-biphenyl]-4-yl)methylene)hydrazine-1-carboximidamide (JM3-67-2)

The mixture of compound (E)-4(2-carbamimidoylhydrazono)methyl)-3,5-dichlorophenyl trifluoromethanesulfonate (150 mg, 0.40 mmol), phenyl boronic acid (622 mg, 0.51 mmol), Pd(PPh₃)₄ (23 mg, 0.02 mmol), and K₂CO₃ (136 mg, 0.99 mmol) in dimethoxyethane/H₂O (4:1) was irradiated at 150° C. for 30 min under microwave conditions. The black residue formed was filtered through Celite and the solvent was concentrated in vacuo. The residue was purified by silica gel chromatography using 80% ethyl acetate in hexanes to yield white powder (8%). ¹H NMR (cd₃od, 400 MHz) δ 8.42 (s, 1H), 7.78 (s, 2H), 7.67 (d, 2H, J=7.6 Hz), 7.50 (t, 2H, J=7.6 Hz), 7.47 (t, 1H, J=7.0 Hz). ¹³C NMR (100 MHz, cd₃od) δ 144.32, 143.04, 137.20, 135.16, 128.94, 128.79, 127.63, 127.07, 126.65, 118.80. ESI-HRMS Calc m/z for C₁₄H₁₃Cl₂N₄ 307.0512 (M+H)⁺, found 307.0507. HPLC 97.88% purity t_(R)=11.87 min.

Example 76 (E)-2-(2-chloro-6-ethylbenzylidene)hydrazine-1-carboximidamide acetate (JM3-81-2)

Light yellow color solid. ¹H NMR (cd₃od, 400 MHz) δ 8.37 (s, 1H), 7.22 (d, 2H, J=5.1 Hz), 7.18 (t, 1H, J=5.1 Hz), 2.83 (q, 2H, J=7.5 Hz), 1.82 (s, 3H), 1.13 (t, 3H, J=7.3 Hz). ¹³C NMR (100 MHz, cd₃od) δ 178.27, 156.67, 145.88, 145.56, 134.43, 130.32, 129.67, 128.08, 127.09, 26.61, 22.19, 14.39. ESI-HRMS Calc m/z for C₁₀H₁₄ClN₄ 225.0902 (M+H)⁺, found 225.0909. HPLC 97.44% purity t_(R)=8.97 min.

Example 77 (E)-2-(2-chloro-6-isopropylbenzylidene)hydrazine-1-carboximidamide acetate (JM3-89-2)

Light yellow solid. ¹H NMR (cd₃od, 400 MHz) δ 8.26 (s, 1H), 7.23 (d, 1H, J=7.0 Hz), 7.16 (t, 2H, J=7.6 Hz), 3.54 (sep, 1H, J=6.4 Hz), 1.80 (s, 3H), 1.14 (d, 6H, J=6.4 Hz). ¹³C NMR (100 MHz, cd₃od) δ 178.63, 161.00, 150.28, 145.29, 133.38, 130.13, 128.22, 126.70, 124.35, 29.23, 22.68, 22.52. ESI-HRMS Calc m/z for C₁₁H₁₆ClN₄ 239.1058 (M+H)⁺, found 239.1068. HPLC 99.63% purity t_(R)=9.90 min.

Example 78 (E)-2-(2,6-diisopropylbenzylidene)hydrazine-1-carboximidamide (JM3-99-2)

Light yellow solid. ¹H NMR (dmso-d₆, 400 MHz) δ 8.33 (s, 1H), 7.24 (t, 1H, J=7.8 Hz), 7.15 (d, 2H, J=7.58 Hz), 5.61 (br s, 2H), 5.41 (br s, 2H), 3.29-3.20 (m, 2H), 1.15 (d, 12H, J=6.8 Hz), ¹³C NMR (100 MHz, dmso-d₆) δ 150.28, 145.29, 133.83, 130.13, 126.70, 124.35, 29.63, 22.68. ESI-HRMS Calc m/z for C₁₄H₂₃N₄ 247.1917 (M+H)⁺, found 247.1918. HPLC 96.12% purity tR=11.42 min.

Example 79 2-(2,6-dichlorobenzyl)-1H-imidazole (JM3-131-2)

To a solution of dimethyl sulfoxide (127 mg, 1.63 mmol) in 7 ml dichloromethane cooled to −78° C. was then added a solution of oxalyl chloride (592 mg, 1.63 mmol) in 7 ml dichloromethane. The mixture was stirred for 50 minutes at −78° C. and then a solution of 2-(2,6-dichlorobenzyl)-4,5-dihydro-1H-imidazole (80 mg, 0.35 mmol) in 8 ml dichloromethane was added and stirring continued at −78° C. for 90 minutes. Then was added trimethylamine (338 mg, 3.34 mmol) and the reaction mixture was warmed to ambient temperature and stirring continued for 2 hours. To this solution was added concentrated aqueous ammonia and the reaction mixture extracted with ethyl acetate extracted and washed with brine, dried over Na₂SO₄, and concentrated in vacuo. The crude was purified on silica column using methanol in dichloromethane as eluent. The final product was obtained as white solid (82%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.75 (br s, 1H), 7.47 (d, 2H, J=8.0 Hz), 7.33 (t, 1H, J=7.8 Hz), 6.97 (s, 1H), 6.70 (s, 1H), 4.25 (s, 2H). ¹³C NMR (100 MHz, dmso-d₆) δ 143.80, 135.81, 134.39, 129.64, 128.84, 127.83, 116.26, 30.68. ESI-HRMS Calc m/z for C₁₀ H₉Cl₂N₂ 227.0137 (M+H)⁺, found 227.0143. HPLC 97.15% purity tR=6.34 min.

Example 80 (E)-2-(2,6-bis(trifluoromethyl)benzylidene)hydrazine-1-carboximidamide acetate (JM3-141-2)

White solid. ¹H NMR (dmso-d₆, 400 MHz) δ 8.25 (s, 1H), 8.07 (d, 2H, J=8.2 Hz), 7.70 (t, 1H, J=8.2 Hz), 6.00 (br s, 2H), 5.84 (br s, 2H), 1.87 (s, 3H). ¹³C NMR (100 MHz, dmso-d₆) δ 172.81, 161.92, 136.03, 131.02, 129.26, 128.96, 125.55, 122.83, 21.78. ESI-HRMS Calc m/z for C₁₀H₉F₆N₄ 299.0726 (M+H)⁺, found 299.0733. HPLC 98.16% purity t_(R)=8.87 min. Example 81. (E)-2-(2-(2,3-dichlorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM3-149-2)

Off-white solid. ¹H NMR (dmso-d₆, 400 MHz) δ 12.58 (br s, 1H), 8.40 (s, 1H), 8.14 (d, 1H, J=7.6 Hz), 7.85 (br s, 2H), 7.60 (d, 1H, J=7.6 Hz), 7.37 (t, 1H, J=7.6 Hz), 3.57 (s, 4H). ¹³C NMR (150 MHz, dmso-d₆) δ 141.89, 141.03, 135.24, 132.61, 130.95, 130.61, 128.45, 126.06, 55.39, 42.83. ESI-HRMS Calc m/z for C₁₀H₁₁Cl₂N₄ 257.0355 (M+H)⁺, found 257.0365. HPLC 99.20% purity t_(R)=9.09 min.

Example 82 (E)-2-(2-(2,3,6-trichlorobenzylidene)hydrazinyl)-4,5-dihydro-1H-imidazole hydrochloride (JM3-151-2)

Light yellow solid. ¹H NMR (dmso-d₆, 400 MHz) δ 12.61 (br s, 1H), 8.63 (s, 2H), 8.38 (s, 1H), 7.77 (d, 1H, J=8.5 Hz), 7.65 (d, 1H, J=8.5 Hz), 7.60 (d, 1H, J=7.6 Hz), 3.72 (s, 4H). ¹³C NMR (100 MHz, dmso-d6) δ 159.25, 144.01, 133.02, 132.71, 132.66, 132.08, 131.92, 130.24, 54.40, 43.26. ESI-HRMS Calc m/z for C₁₀H₁₀Cl₃N₄ 290.9966 (M+H)⁺, found 290.9963. HPLC 98.06% purity t_(R)=9.20 min.

Example 83 (E)-2-(2-(2,3-dichlorobenzylidene)hydrazinyl)-1,4,5,6-tetrahydropyrimidine hydrochloride (JM3-153-2)

Light yellow solid (40%). ¹H NMR (dmso-d₆, 400 MHz) δ 12.44 (s, 1H), 8.59 (s, 3H), 8.29 (d, 1H, J=7.9 Hz), 7.73 (d, 1H, J=7.9 Hz), 7.45 (t, 1H, J=7.9 Hz), 3.38 (t, 4H, J=5.1 Hz), 1.92 (m, 2H). ¹³C NMR (100 MHz, dmso-d6) δ 155.41, 141.78, 133.81, 132.77, 132.22, 131.42, 128.69, 126.57, 38.49, 19.91. ESI-HRMS Calc m/z for C₁₁H₁₃Cl₂N₄ 271.0512 (M+H)⁺, found 271.0509. HPLC 98.21% purity t_(R)=9.65 min.

Example 84 (E)-2-(2-(2,3,6-trichlorobenzylidene)hydrazinyl)-1,4,5,6-tetrahydropyrimidine hydrochloride (JM3-155-2)

White solid (40%). ¹H NMR (dmso-d₆, 400 MHz) δ 12.38 (s, 1H), 8.41 (s, 1H), 8.40 (br s, 2H), 7.82 (d, 1H, J=8.8 Hz), 7.69 (d, 1H, J=8.8 Hz), 3.40 (m, 4H), 1.95 (m, 2H). ¹³C NMR (100 MHz, dmso-d6) δ 151.47, 141.88, 133.08, 132.87, 132.73, 132.14, 131.88, 130.17, 38.60, 19.82. ESI-HRMS Calc m/z for C₁₁H₁₂Cl₃N₄ 305.0122 (M+H)⁺, found 305.0132. HPLC 98.10% purity tR=9.77 min.

Example 85 (E)-N-butyl-2-(2,6-dichlorobenzylidene)hydrazine-1-carboximidamide hydroiodide (JM3-161-2)

To a solution of methyl-2-(2,6-dichlorobenzylidene)hydrazine-1-carbimidothioate hydroiodide (150 mg, 0.38 mmol) in EtOH (4 mL) was added n-butyl amine (56.2 mg, 0.77 mmol). The reaction mixture was stirred at reflux for overnight. The EtOH was evaporated and triturated with ether to yield crude product as precipitate. The crude was purified by silica gel chromatography using 0-10% methanol in dichloromethane to yield final compound as white solid (50 mg, 32%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.71 (s, 1H), 8.41 (s, 1H), 7.93 (br s, 1H), 7.86 (br s, 2H), 7.60 (d, 2H, J=7.8 Hz), 7.48 (t, 1H, J=7.3 Hz), 3.26 (q, 2H, J=6.8 Hz), 1.57-1.47 (m, 2H), 1.38-1.28 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). ¹³C NMR (100 MHz, dmso-d6) δ 154.35, 140.93, 134.52, 132.12, 130.37, 129.57, 41.24, 30.94, 19.69, 14.03. ESI-HRMS Calc m/z for C₁₂H₁₇Cl₂N₄ 287.0825 (M+H)⁺, found 287.0820. HPLC 97.03% purity t_(R)=10.52 min.

Example 86 2-(2,3-dichlorobenzyl)-4,5-dihydro-1H-imidazole (JM3-179-2)

Light yellow solid. ¹H NMR (dmso-d₆, 400 MHz) δ 7.51 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.0 Hz), 7.30 (t, 1H, J=7.8 Hz), 5.91 (br s, 1H), 3.61 (s, 2H), 3.10 (s, 4H). ¹³C NMR (100 MHz, dmso-d₆) δ 164.71, 138.25, 131.98, 130.44, 129.19, 128.29, 52.16, 34.14. ESI-HRMS Calc m/z for C₁₀H₁₁Cl₂N₂ 229.0294 (M+H)⁺, found 229.0289 HPLC 96.02% purity t_(R)=7.14 min.

Example 87 2-(2,3-dichlorobenzyl)-1,4,5,6-tetrahydropyrimidine (JM3-181-2)

Brown solid. ¹H NMR (dmso-d₆, 400 MHz) δ 7.53 (d, 1H, J=7.5 Hz), 7.36 (d, 1H, J=7.5 Hz), 7.31 (t, 1H, J=7.5 Hz), 3.57 (s, 2H), 3.19 (t, 4H, J=5.6 Hz), 1.7-1.63 (m, 2H). ¹³C NMR (100 MHz, dmso-d₆) δ 156.24, 137.71, 132.02, 130.39, 129.34, 128.40, 55.39, 40.83, 20.10. ESI-HRMS Calc m/z for C₁₁H₁₃Cl₂N₂ 243.0450 (M+H)⁺, found 243.0460 HPLC 96.12% purity t_(R)=7.54 min.

Example 88 (E)-2-(2-iodobenzylidene)hydrazine-1-carboximidamide acetate (JM3-183-2)

White powder. ¹H NMR (dmso-d₆, 400 MHz) δ 8.20 (s, 1H), 8.10 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=7.0 Hz), 7.38 (t, 1H, J=7.3 Hz), 7.08 (t, 1H, J=7.0 Hz), 6.85 (br s, 4H), 1.86 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 174.03, 159.67, 147.15, 139.86, 137.28, 130.89, 128.64, 127.70, 99.67, 22.69. ESI-HRMS Calc m/z for C₈H₁₀IN₄ 288.9945 (M+H)⁺, found 288.9951. HPLC 97.03% purity t_(R)=8.62 min.

Examples 89-100 were prepare using the following general procedure.

Reagents and conditions: (i) ethyl acetoacetate or ethyl 2-methylacetoacetate (1.2 eq), toluene, reflux, overnight, 30-75%.

A solution of compound 1 as an acetic acid salt (1 eq) and ethyl acetoacetate or ethyl 2-methylacetoacetate (1.2 eq) in toluene was refluxed for overnight. The solvent was evaporated and purified on silica with 0-15% methanol in dichloromethane to yield final compound 2 as solid.

Example 89 (E)-2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-5,6-dimethylpyrimidin-4(1H)-one (JM3-191-2)

White powder (38%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.59 (br s, 2H), 8.26 (s, 1H), 7.54 (d, 2H, J=8.2 Hz), 7.39 (t, 1H, J=8.2 Hz), 2.11 (s, 3H), 1.81 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ161.90, 161.20, 153.02, 141.23, 133.60, 130.25, 129.90, 127.68, 102.37, 21.02, 11.30. ESI-HRMS Calc m/z for C₁₃H₁₃Cl₂N₄o 311.0461 (M+H)⁺, found 311.0469. HPLC 97.1% purity t_(R)=10.35 min.

Example 90 (E)-2-(2-(2,3-dichlorobenzylidene)hydrazinyl)-5,6-dimethylpyrimidin-4(1H)-one (JM3-195-2)

White solid (43%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.53 (br s, 2H), 8.62 (d, 1H, J=7.5 Hz), 8.42 (s, 1H), 7.63 (d, 1H, J=7.5 Hz), 7.38 (t, 1H, J=7.8 Hz), 2.13 (s, 3H), 1.85 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 163.26, 159.06, 152.25, 133.89, 133.56, 129.95, 129.57, 124.58, 119.26, 118.20, 102.67, 20.25, 11.05. ESI-HRMS Calc m/z for C₁₃H₁₃Cl₂N₄o 311.0461 (M+H)⁺, found 311.0467. HPLC 96.58% purity t_(R)=11.03 min.

Example 91 (E)-2-(2-(2,6-dichlorobenzylidene)hydrazinyl)-6-methylpyrimidin-4(1H)-one (JM3-197-2)

White solid (40%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.68 (br s, 2H), 8.32 (s, 1H), 7.58 (d, 2H, J=8.0 Hz), 7.43 (t, 1H, J=7.8 Hz), 5.56 (s, 1H), 2.10 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 161.92, 161.26, 152.95, 141.02, 133.45, 130.05, 129.75, 126.59, 102.65, 21.02. ESI-HRMS Calc m/z for C₁₂H₁₁Cl₂N₄o 297.0304 (M+H)⁺, found 297.0296. HPLC 96.28% purity t_(R)=10.34 min.

Example 92 (E)-2-(2-(2,3-dichlorobenzylidene)hydrazinyl)-6-methylpyrimidin-4(1H)-one (JM3-199-2)

Off-White solid (46%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.52 (br s, 2H), 8.67 (d, 1H, J=7.8 Hz), 8.52 (s, 1H), 7.71 (d, 1H, J=7.8 Hz), 7.44 (t, 1H, J=8.0 Hz), 5.62 (s, 1H), 2.15 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 162.93, 159.65, 152.05, 133.75, 133.25, 131.05, 129.98, 125.70, 119.78, 118.93, 103.05, 20.58. ESI-HRMS Calc m/z for C₁₂H₁₁Cl₂N₄o 297.0304 (M+H)⁺, found 297.0315. HPLC 97.68% purity t_(R)=10.22 min.

Example 93 (E)-6-methyl-2-(2-(2,3,6-trichlorobenzylidene)hydrazinyl)pyrimidin-4(1H)-one (JM3-201-2)

White solid (75%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.30 (br s, 2H), 8.27 (s, 1H), 7.69 (d, 1H, J=8.5 Hz), 7.60 (d, 1H, J=8.5 Hz), 5.55 (s, 1H), 1.81 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 162.07, 153.05, 134.48, 133.16, 132.99, 132.84, 132.59, 132.01, 131.44, 130.36, 102.75, 19.09. ESI-HRMS Calc m/z for C₁₂H₁₀Cl₃N₄o 330.9915 (M+H)⁺, found 330.9912. HPLC 98.51% purity t_(R)=11.48 min.

Example 94 (E)-2-(2-(2-chloro-6-fluorobenzylidene)hydrazinyl)-6-methylpyrimidin-4(1H)-one (JM3-203-2)

White solid (33%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.62 (br s, 2H), 8.32 (s, 1H), 7.50-7.30 (m, 3H), 5.57 (s, 1H), 2.11 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 163.07, 156.89, 152.06, 138.50, 136.54, 130.28, 129.03, 128.90, 117.25, 115.35, 103.20, 20.28. ESI-HRMS Calc m/z for C₁₂H₁₁ClFN₄o 281.0600 (M+H)⁺, found 281.0595. HPLC 98.06% purity t_(R)=9.34 min.

Example 95 (E)-5,6-dimethyl-2-(2-(2,3,6-trichlorobenzylidene)hydrazinyl)pyrimidin-4(1H)-one (JM3-205-7)

Light yellow solid (75%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.48 (br s, 2H), 8.23 (s, 1H), 7.69 (d, 1H, J=8.5 Hz), 7.59 (d, 1H, J=8.5 Hz), 2.14 (s, 3H), 1.83 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 162.26, 153.92, 138.96, 134.02, 132.92, 132.06, 132.02, 131.35, 129.05, 128.95, 102.75, 19.09, 11.06. ESI-HRMS Calc m/z for C₁₃H₁₂Cl₃N₄o 340.0071 (M+H)⁺, found 340.0066. HPLC 96.57% purity t_(R)=11.05 min.

Example 96 (E)-2-(2-(2-chloro-6-fluorobenzylidene)hydrazinyl)-5,6-dimethylpyrimidin-4(1H)-one (JM3-207-2)

White solid (31%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.61 (br s, 2H), 8.28 (s, 1H), 7.53-7.30 (m, 3H), 2.14 (s, 3H), 1.84 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 162.98, 156.06, 151.96, 138.05, 136.03, 129.97, 128.95, 128.02, 118.03, 115.59, 105. 26, 20.25, 11.36. ESI-HRMS Calc m/z for C₁₃H₁₃ClFN₄o 295.0756 (M+H)⁺, found 295.0764. HPLC 97.57% purity t_(R)=9.58 min.

Example 97 (E)-2-(2-(3,4-dichlorobenzylidene)hydrazinyl)-5,6-dimethylpyrimidin-4(1H)-one (JM3-209-2)

White solid (37%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.49 (br s, 2H), 8.42 (s, 1H), 7.98 (s, 1H), 7.81 (d, 1H, J=8.3 Hz), 7.65 (d, 1H, J=8.5 Hz), 2.11 (s, 3H), 1.84 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 173.96, 159.67, 147.25, 139.65, 138.03, 130.26, 128.98, 127.62, 102.67, 22.03, 10.59. ESI-HRMS Calc m/z for C₁₃H₁₃Cl₂N₄o 311.0461 (M+H)⁺, found 311.0465. HPLC 98.20% purity t_(R)=11.33 min.

Example 98 (E)-2-(2-(3,4-dichlorobenzylidene)hydrazinyl)-6-methylpyrimidin-4(1H)-one (JM3-211-2)

White solid (62%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.42 (br s, 2H), 8.43 (s, 1H), 8.02 (s, 1H), 7.83 (d, 1H, J=8.5 Hz), 7.64 (d, 1H, J=8.5 Hz), 5.52 (s, 1H), 2.08 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 174.03, 159.67, 147.15, 139.86, 137.28, 130.89, 128.64, 127.70, 99.67, 22.69. ESI-HRMS Calc m/z for C₁₂H₁₁Cl₂N₄o 297.0304 (M+H)⁺, found 297.0306. HPLC 98.75% purity tR=11.02 min.

Example 99 (E)-2-(2-(2-chlorobenzylidene)hydrazinyl)-5,6-dimethylpyrimidin-4(1H)-one (JM3-213-2)

White solid (31%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.60 (br s, 2H), 8.59 (d, 1H, J=7.3 Hz), 8.40 (s, 1H), 7.45 (d, 1H, J=7.3 Hz), 7.42-7.34 (m, 2H), 2.11 (s, 3H), 1.85 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 172.09, 162.85, 152.78, 140.23, 133.52, 131.85, 131.00, 129.906, 128.29, 127.68, 104.39, 21.68, 11.03. ESI-HRMS Calc m/z for C₁₃H₁₄ClN₄o 277.0851 (M+H)⁺, found 277.0852. HPLC 98.53% purity t_(R)=9.72 min.

Example 100 (E)-2-(2-(2-chlorobenzylidene)hydrazinyl)-6-methylpyrimidin-4(1H)-one (JM3-215-2)

Off-white solid (33%). ¹H NMR (dmso-d₆, 400 MHz) δ 11.63 (br s, 2H), 8.61 (d, 1H, J=7.3 Hz), 8.44 (s, 1H), 7.47 (d, 1H, J=7.3 Hz), 7.43-7.35 (m, 2H), 5.56 (s, 1H), 2.09 (s, 3H). ¹³C NMR (100 MHz, dmso-d6) δ 172.47, 162.91, 152.95, 140.60, 133.00, 132.07, 131.38, 129.99, 128.72, 127.64, 102.38, 21.53. ESI-HRMS Calc m/z for C₁₂H₁₂ClN₄o 263.0644 (M+H)⁺, found 263.0702. HPLC 99.10% purity t_(R)=9.34 min.

Example 101 (E)-2-(2-bromobenzylidene)hydrazine-1-carboxamide hydrochloride (JM3-219-2)

White crystals (88%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.51 (s, 1H), 8.20 (s, 1H), 8.17 (d, 1H, J=8.0 Hz), 7.61 (d, 1H, J=7.6 Hz), 7.38 (t, 1H, J=7.3 Hz), 7.28 (t, 1H, J=8.0 Hz), 6.57 (br s, 2H). ¹³C NMR (100 MHz, dmso-d6) δ 156.99, 137.93, 133.89, 133.35, 131.12, 128.25, 127.83, 123.12. ESI-HRMS Calc m/z for C₈H₉BrN₃O 241.9924 (M+H)⁺, found 241.9930. HPLC 99.23% purity t_(R)=9.40 min.

Example 102 (E)-2-(2-fluorobenzylidene)hydrazine-1-carboxamide hydrochloride (JM3-221-2)

White crystals (87%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.42 (s, 1H), 8.12 (t, 1H, J=7.5 Hz), 8.06 (s, 1H), 7.44-7.35 (m, 1H), 7.27-7.18 (m, 2H), 6.56 (br s, 2H). ¹³C NMR (100 MHz, dmso-d6) δ 161.96, 159.50, 157.05, 132.11, 131.18, 126.86, 125.06, 122.82, 116.26. ESI-HRMS Calc m/z for C₈H₉FN₃O 182.0724 (M+H)⁺, found 182.0729. HPLC 99.51% purity t_(R)=8.97 min.

Example 103 (E)-2-(2-chlorobenzylidene)hydrazine-1-carboxamide hydrochloride (JM3-223-2)

White crystals (78%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.49 (s, 1H), 8.24 (s, 1H), 8.22-8.18 (m, 1H), 7.49-7.43 (m, 1H), 7.40-7.32 (m, 2H), 6.56 (br s, 2H). ¹³C NMR (100 MHz, dmso-d6) δ 157.00, 135.52, 132.70, 132.40, 130.83, 130.11, 127.75, 127.43. ESI-HRMS Calc m/z for C₈H₉ClN₃O 198.0423 (M+H)⁺, found 198.0435. HPLC 99.26% purity t_(R)=10.00 min.

Example 104. (E)-2-(2-iodobenzylidene)hydrazine-1-carboxamide hydrochloride (JM3-225-2)

White crystals (71%). ¹H NMR (dmso-d₆, 400 MHz) δ 10.51 (s, 1H), 8.10-8.06 (m, 2H), 7.87 (d, 1H, J=7.8 Hz), 7.39 (t, 1H, J=7.8 Hz), 7.10 (t, 1H, J=7.8 Hz), 6.54 (br s, 2H). ¹³C NMR (100 MHz, dmso-d6) δ 157.00, 142.57, 139.91, 136.67, 131.22, 128.76, 127.61, 99.49. ESI-HRMS Calc m/z for C₈H₉IN₃O 289.9785 (M+H)⁻, found 289.9786. HPLC 99.01% purity t_(R)=10.82 min.

Example 105 2-(2,6-dichlorobenzyl)hydrazine-1-carboximidamide (JM3-227-2)

A solution of 1,3-dichloro-2-(chloromethyl)benzene (100 mg, 0.51 mmol) and aminoguanidine bicarbonate (69 mg, 0.51 mmol) was refluxed overnight in EtOH (5 mL). The solvent was evaporated and purified on silica with 0-10% methanol in dichloromethane to yield final compound as white solid (60%). ¹H NMR (cd₃od, 600 MHz) δ 7.53 (d, 2H, J=7.58 Hz), 7.32 (t, 1H, J=7.09 Hz), 5.04 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.74, 136.89, 131.10, 128.89, 128.48, 48.90. ESI-HRMS Calc m/z for C₈H₁₁Cl₂N₄ 233.0355 (M+H)⁺, found 233.0350. HPLC 96.78% purity t_(R)=6.52 min.

Example 106 (E)-2-(2-(2,6-dichlorophenyl)ethylidene)hydrazine-1-carboximidamide acetate (JM3-239-2)

White solid (53%). ¹H NMR (dmso-d₆, 400 MHz) δ 7.49 (d, 2H, J=8.1 Hz), 7.38-7.30 (m, 2H), 6.64 (br s, 4H), 3.85 (d, 2H, J=4.9 Hz), 1.79 (s, 3H). ¹³C NMR (100 MHz, dmso-d₆) δ 174.75, 158.28, 143.42, 135.39, 129.88, 128.99, 34.38, 23.25. ESI-HRMS Calc m/z for C₉H₁₁Cl₂N₄ 245.0355 (M+H)⁻, found 245.0350. HPLC 98.05% purity t_(R)=6.58 min.

Example 107 (E)-1-((2,6-dichlorobenzylidene)amino)tetrahydropyrimidin-2(1H)-imine hydrobromide (JM3-255-2)

A solution of (E)-2-(2,6-dichlorobenzylidene)hydrazine-1-carboximidamide (150 mg, 0.65 mmol) and 1,3-dibrmopropane (261 mg, 1.24 mmol) in EtOH (5 mL) was refluxed for overnight. The solvent was evaporated to yield a white compound. The resulted crude was purified on silica with 0-5% methanol in dichloromethane to yield final compound as white solid (63%). ¹H NMR (dmso-d₆, 400 MHz) δ 8.23 (s, 1H), 7.62 (d, 2H, J=7.8 Hz), 7.50 (t, 1H, J=7.5 Hz), 3.83 (t, 2H, J=6.1 Hz), 3.35 (t, 2H, J=5.6 Hz), 2.17 (p, 2H, J=6.1 Hz). ¹³C NMR (100 MHz, dmso-d₆) δ 155.34, 139.47, 134.54, 132.18, 130.54, 129.63, 42.78, 37.48, 20.32. ESI-HRMS Calc m/z for C₁₁H₁₃Cl₂N₄ 271.0512 (M+H)⁻, found 271.0510. HPLC 98.65% purity t_(R)=8.94 min. ¹NMR (CDCl₃, 400 MHz) δ 9.73 (br s, 1H), 8.73 (br s, 1H), 8.11 (s, 1H), 7.44 (d, 2H, J=7.8 Hz), 7.32 (t, 1H, J=7.3 Hz), 6.71 (br s, 1H), 3.82 (t, 2H, J=6.1 Hz), 3.53 (t, 2H, J=5.8 Hz), 2.34 (p, 2H, J=6.1 Hz). ¹³C NMR (100 MHz, CDCl₃) δ 154.06, 137.93, 135.10, 131.26, 129.55, 128.34, 41.70, 37.25, 20.19. (Reported structure was confirmed by HMBC. Correlations were observed for H2/C1, H2/C5 and H4/C5).

Example 108 (E)-2-(2,6-dichlorobenzylidene)-1-methylhydrazine-1-carboximidamide hydroiodide (JM3-257-2)

A solution of (E)-2-(2,6-dichlorobenzylidene)hydrazine-1-carboximidamide (200 mg, 0.86 mmol) and excess amount of methyl iodide in EtOH (3 mL) was refluxed for overnight. The solvent was evaporated and washed with dichloromethane followed by ether to yield final compound as off-white solid (62%). 41 NMR (dmso-d₆, 400 MHz) δ 8.19 (s, 1H), 7.91 (br s, 4H), 7.62 (d, 2H, J=8.1 Hz), 7.50 (t, 1H, J=7.5 Hz), 3.47 (s, 3H). ¹³C NMR (100 MHz, dmso-d₆) δ 156.70, 140.33, 134.53, 132.19, 130.47, 129.64, 32.08. ESI-HRMS Calc m/z for C₉H₁₁Cl₂N₄ 245.0355 (M+H)⁻, found 245.0349. HPLC 99.25% purity t_(R)=8.41 min.

Example 109 (E)-2-(2,6-diethylbenzylidene)hydrazine-1-carboximidamide (JM2-233-2)

Yellow solid (49%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.29 (s, 1H), 7.09 (t, 1H, J=7.0 Hz), 7.01 (d, 2H, J=7.6 Hz), 5.58 (br s, 2H), 5.38 (br s, 2H), 2.70 (q, 4H, J=7.0 Hz), 1.09 (t, 6H, J=7.6 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 159.25, 144.46, 143.22, 132.35, 128.40, 127.14, 27.02, 16.15. ESI-HRMS Calc m/z for C₁₂H₁₉N₄ 219.1604 (M+H)⁺, found 219.1615. HPLC 96.24% purity t_(R)=7.95 min.

Example 110 Methyl (E)-2-(2,6-dichlorobenzylidene)hydrazine-1-carbimidothioate hydroiodide (JM2-169-2)

To a solution of 2-(2,6-dichlorobenzylidene)hydrazine-1-carbothioamide (400 mg, 1.61 mmol) in DMF (3 mL) was added iodomethane (454 mg, 3.22 mmol). The reaction mixture was stirred at 50° C. for 20 h. The DMF was evaporated under vacuum and the crude was triturated with ether to have a brown precipitate which was filtered and washed with ether to get the desired compound as yellow powder (99%). ¹H NMR (dmso-d₆, 600 MHz) δ 13.22 (s, 1H), 9.34 (br s, 2H), 8.53 (s, 1H), 7.58 (d, 1H, J=7.0 Hz), 7.48 (t, 1H, J=6.4 Hz), 2.68 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 167.65, 148.48, 134.59, 132.73, 139.98, 129.53, 13.92. ESI-MS (M+H)⁺ 262.01.

Example 111 (E)-2-(2,6-dichlorobenzylidene)-N-methylhydrazine-1-carboximidamide hydroiodide (JM2-171-2)

To a solution of methyl-2-(2,6-dichlorobenzylidene)hydrazine-1-carbimidothioate hydroiodide (200 mg, 0.51 mmol) in EtOH (4 mL) was added methylamine (24 mg, 0.79 mmol). The reaction mixture was stirred at reflux for overnight. The EtOH was evaporated and triturated with ether to yield crude product as precipitate. The crude was purified by silica gel chromatography using 10% methanol in dichloromethane to yield final compound as yellow solid (50 mg, 63%). ¹H NMR (dmso-d₆, 600 MHz) δ 11.79 (s, 1H), 8.38 (s, 1H), 7.90 (br s, 1H), 7.84 (br s, 2H), 7.57 (d, 2H, J=8.2 Hz), 7.46 (t, 1H, J=8.2 Hz), 2.84 (d, 3H, J=4.1 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 155.51, 134.45, 133.47, 131.95, 130.51, 129.48, 28.62. ESI-HRMS Calc m/z for C₉H₁₁CL₂N₄ 245.0355 (M+H)⁺, found 245.0537. HPLC 99.30% purity t_(R)=7.14 min.

Example 112 (E)-2-(naphthalen-2-ylmethylene)hydrazine-1-carboximidamide acetate (JM1-111-2)

White powder. ¹H NMR (dmso-d₆, 600 MHz) δ 8.15 (s, 1H), 8.06 (d, 1H, J=8.8 Hz), 7.98 (s, 1H), 7.98-7.81 (m, 3H), 7.51-7.43 (m, 2H), 6.51 (br s, 4H), 1.81 (s, 3H). ¹³C NMR (150 MHz, cd₃od) δ 179.52, 156.27, 147.36, 134.46, 133.13, 131.30, 129.13, 128.17, 128.09, 127.43, 126.92, 126.80, 122.37, 22.88. ESI-HRMS Calc m/z for C₂H₁₃N₄ 213.1135 (M+H)⁺, found 231.1145. HPLC 99.56% purity t_(R)=6.21 min.

Example 113 (E)-2-(2-chloro-6-fluorobenzylidene)hydrazine-1-carbothioamide (JM1-113-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.26 (s, 1H), 7.43 (d, 2H, J=6.4 Hz), 7.32 (t, 1H, J=9.4 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 178.79, 161.61, 159.91, 135.90, 134.02, 131.91, 126.63, 120.80, 115.83. ESI-HRMS Calc m/z for C₈H₈ClFN₃S 232.1016 (M+H)⁺, found 232.0111. HPLC 99.74% purity t_(R)=6.21 min.

Example 114 (E)-2-(2,6-dichlorobenzylidene)hydrazine-1-carbothioamide (JM1-115-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.27 (s, 1H), 7.36 (q, 1H, J=8.2 Hz), 7.30 (d, 1H, J=8.2 Hz), 7.13 (t, 1H, J=7.6 Hz), 7.05 (d, 2H, 7.04 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 178.92, 138.07, 134.42, 131.46, 130.24, 129.67. ESI-HRMS Calc m/z for C₈H₈Cl₂N₄S 247.9810 (M+H)⁺, found 247.9812. HPLC 98.01% purity t_(R)=10.74 min.

Example 115. (E)-2-(2,6-dimethylbenzylidene)hydrazine-1-carbothioamide (JM1-121-2)

White powder. ¹H NMR (dmso-d₆, 600 MHz) δ 11.31 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.37 (s, 1H), 7.43 (d, 2H, J=6.4 Hz), 7.32 (t, 1H, J=9.4 Hz), 2.36 (s, 6H). ¹³C NMR (150 MHz, dmso-d₆) δ 178.26, 143.63, 137.77, 131.13, 129.16, 129.03, 21.48. ESI-HRMS Calc m/z for C₁₀H₁₄N₃S 208.0903 (M+H)⁻, found 208.0907. HPLC 96.79% purity t_(R)=10.66 min.

Example 116 (E)-2-(2-chloro-6-nitrobenzylidene)hydrazine-1-carbothioamide (JM1-125-2)

Yellow powder. ¹H NMR (cd₃od, 600 MHz) δ 8.26 (s, 1H), 7.73 (d, 1H, J=8.2 Hz), 7.70 (d, 1H, J=7.6 Hz), 7.78 (t, 1H, J=7.6 Hz). ¹³C NMR (150 MHz, cd₃od) δ 179.42, 170.36, 149.53, 135.24, 132.87, 130.87, 124.81, 122.13. ESI-HRMS Calc m/z for C₈H₈ClN₄O₂S 259.0051 (M+H)⁺, found 259.0045. HPLC 98.40% purity t_(R)=9.90 min.

Example 117 (E)-2-(2,6-dibromobenzylidene)hydrazine-1-carbothioamide (JM1-127-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.23 (s, 1H), 7.70 (d, 2H, J=7.6 Hz), 7.24 (t, 1H, J=8.2 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 178.92, 141.17, 133.38, 133.28, 132.16, 123.88. ESI-HRMS Calc m/z for C₈H₈Br₂N₃S 335.8800 (M+H)⁺, found 335.8809. HPLC 99.44% purity t_(R)=11.07 min.

Example 118 (E)-2-(naphthalen-2-ylmethylene)hydrazine-1-carbothioamide (JM1-129-2)

White powder. ¹H NMR (dmso-d₆, 600 MHz) δ 11.49 (s, 1H), 8.20 (d, 2H, J=18.2 Hz), 8.15 (d, 1H, J=8.8 Hz), 8.07 (d, 2H, J=16.4 Hz), 7.94-7.91 (m, 1H), 7.90-7.86 (m, 2H), 7.53-7.49 (m, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 178.43, 142.46, 134.06, 133.28, 132.45, 129.26, 128.64, 127.40, 127.06, 123.54. ESI-HRMS Calc m/z for C₁₂H₁₂N₃S 230.0746 (M+H)⁻, found 230.0752. HPLC 97.13% purity t_(R)=10.94 min.

Example 119 (E)-2-(2-fluorobenzylidene)hydrazine-1-carbothioamide (JM1-135-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.22 (s, 1H), 8.05 (t, 1H, J=9.4 Hz), 7.41 (q, 1H, J=7.0 Hz), 7.20 (t, 1H, J=7.6 Hz), 7.13 (t, 1H, J=8.2 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 178.59, 162.07, 160.40, 135.22, 135.03, 132.17, 131.95, 127.35, 127.14, 125.25, 124.90, 122.77, 115.94. ESI-HRMS Calc m/z for C₈H₉FN₃S 198.0496 (M+H)⁻, found 198.0500. HPLC 99.85% purity t_(R)=9.34 min.

Example 120 (E)-2-(2,6-dichlorobenzylidene)hydrazine-1-carboximidamide 2,2,2-trifluoroacetate (JM1-141-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.25 (s, 1H), 7.48 (d, 2H, J=7.6 Hz), 7.38 (t, 1H, J=8.8 Hz). ¹³C NMR (150 MHz, cd₃od) δ 155.97, 146.09, 132.74, 132.53, 131.58, 123.39. ESI-HRMS Calc m/z for C₈H₉Cl₂N₄ 231.0199 (M+H)⁺, found 231.0201. HPLC 98.90% purity t_(R)=6.66 min.

Example 121 (E)-2-(2,6-dibromobenzylidene)hydrazine-1-carboximidamide 2,2,2-trifluoroacetate (JM1-143-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.75 (s, 1H), 8.21 (d, 2H, J=7.6 Hz), 7.74 (t, 1H, J=7.0 Hz). ¹³C NMR (150 MHz, cd₃od) δ 155.95, 143.00, 134.72, 131.00, 129.38, 128.80. ESI-HRMS Calc m/z for C₈H₉Br₂N₄ 318.9188 (M+H)⁺, 318.9183. HPLC 98.95% purity t_(R)=5.29 min.

Example 122 (E)-2-(2-bromo-6-nitrobenzylidene)hydrazine-1-carboximidamide acetate (JM1-175-2)

Yellow powder. ¹H NMR (cd₃od, 600 MHz) δ 8.27 (s, 1H), 7.89 (d, 1H, J=8.2 Hz), 7.71 (d, 1H, J=8.2 Hz), 7.43 (t, 1H, J=7.6 Hz), 1.92 (s, 3H). ¹³C NMR (150 MHz, cd₃od) δ 178.62, 157.98, 149.76, 141.22, 136.28, 130.64, 127.34, 124.06, 122.81, 22.27. ESI-HRMS Calc m/z for C₈H₉BrN₅O₂ 285.9934 (M+H)⁺, found 285.9936. HPLC 98.86% purity t_(R)=5.53 min.

Example 123 1-((2,6-dichlorobenzyl)thio)guanidine (JM1-177-2)

1,3-dichloro-2-(chloromethyl)benzene (500 mg, 2.5 mmol) and thiourea (194.6 mg, 2.5 mmol) was dissolved in EtOH (4 mL), added few drops of AcOH. The reaction mixture was refluxed for 2 h, then cooled to room temperature. The precipitated compound was filtered and recrystallized from EtOH to yield final compound as white color powder. The compound was obtained as HCl salt (580 mg, 84%). ¹H NMR (dmso-d₆, 600 MHz) δ 9.42 (s, 4H), 7.53 (d, 2H, J=7.6 Hz), 7.42 (d, 1H, J=8.2 Hz), 4.65 (s, 2H). ¹³C NMR (150 MHz, cd₃od) δ 178.652, 157.98, 149.76, 141.22, 136.28, 130.64, 130.64, 127.34, 124.06, 122.81, 22.27. ESI-HRMS Calc m/z for C₈H₉Cl₂N₂S 234.9858 (M+H)⁺, found 234.9864. HPLC 98.17% purity t_(R)=14.74 min.

Example 124 (E)-2-(2-fluoro-6-nitrobenzylidene)hydrazine-1-carboximidamide acetate (JM1-179-2)

Yellow powder. ¹H NMR (cd₃od, 600 MHz) δ 8.14 (s, 1H), 7.60 (d, 1H, J=8.2 Hz), 7.11 (q, 1H, J=7.6 Hz), 7.42 (t, 1H, J=9.3 Hz), 1.84 (s, 3H). ¹³C NMR (150 MHz, cd₃od) δ 178.75, 161.23, 159.54, 157.22, 148.78, 136.77, 131.20, 119.69, 118.64, 22.27. ESI-HRMS Calc m/z for C₈H₉FN₅O₂ 226.0735 (M+H)⁺, found 226.0738. HPLC 98.25% purity t_(R)=4.71 min.

Example 125 (E)-2-(2-chloro-5-fluorobenzylidene)hydrazine-1-carboximidamide acetate (JM1-185-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.14 (s, 1H), 7.96 (d, 1H, J=9.3 Hz), 7.47-7.43 (m, 1H), 7.16 (t, 1H, J=8.8 Hz), 1.91 (s, 3H). ¹³C NMR (150 MHz, cd₃od) δ 179.10, 162.28, 160.66, 156.75, 142.04, 133.03, 132.97, 131.25, 131.20, 128.94, 118.27, 118.12, 113.33, 113.17, 22.52. ESI-HRMS Calc m/z for C₈H₉ClFN₄ 215.0494 (M+H)⁺, found 0498. HPLC 98.50% purity tR=5.10 min.

Example 126 (E)-2-(2,6-difluorobenzylidene)hydrazine-1-carboximidamide acetate (JM1-191-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.26 (s, 1H), 7.48-7.41 (m, 1H), 7.05 (t, 2H, J=8.0 Hz), 1.93 (s, 3H). ¹³C NMR (150 MHz, cd₃od) δ 179.29, 181.86, 160.16, 156.58, 137.17, 131.68, 111.74, 111.60, 111.03, 22.59. ESI-HRMS Calc m/z for C₈H₉F₂N₄ 199.0790 (M+H)⁺, found 199.0793. HPLC 99.5% purity t_(R)=4.63 min.

Example 127 (E)-2-(2-fluoro-6-methylbenzylidene)hydrazine-1-carboximidamide acetate (JM1-195-2)

White powder. ¹H NMR (cd₃od, 600 MHz) δ 8.42 (s, 1H), 7.28 (q, 1H, J=7.6 Hz), 7.05 (d, 1H, J=7.6 Hz), 6.98 (t, 1H, J=9.9 Hz), 2.54 (s, 3H), 1.92 (s, 3H). ¹³C NMR (150 MHz, cd₃od) δ 179.21, 162.80, 161.14, 156.32, 142.21, 139.91, 130.77, 126.73, 119.61, 112.85, 112.85, 22.62, 20.53. ESI-HRMS Calc m/z for C₉H₁₂FN₄ 195.1041 (M+H)⁺, found 195.1045. HPLC 98.8% purity t_(R)=5.50 min.

Example 128 1-(2,6-dichlorophenyl)-1H-pyrazol-5-amine (JM1-217-2)

(2,6-dichlorophenyl)hydrazine hydrochloride (600 mg, 2.81 mmol) and 3,3-diethoxypropanenitrile (400 mg, 2.79 mmol) were dissolved in 20 mL ethanol and refluxed for 18 h. The solvent was evaporated and residue was purified by silica gel chromatography using DCM/MeOH, to obtain final compound as off-white compound (430 mg, 68%). ¹H NMR (dmso-d₆, 600 MHz) δ 7.77 (br s, 1H), 7.69 (d, 2H, J=8.2 Hz), 7.61 (t, 1H, J=8.2 Hz), 5.60 (s, 1H). ¹³C NMR (150 MHz, dmso-d₆) δ 151.30, 141.51, 139.01, 135.47, 134.02, 129.80, 89.77. ESI-HRMS Calc m/z for C₉H₉Cl₂N₃ 228.0090 (M+H)⁺, found 228.0095.

Example 129 (E)-2-(2,6-diethylbenzylidene)hydrazine-1-carboximidamide (JM2-233-2)

Yellow solid (49%). ¹H NMR (dmso-d₆, 600 MHz) δ 8.29 (s, 1H), 7.09 (t, 1H, J=7.0 Hz), 7.01 (d, 2H, J=7.6 Hz), 5.58 (br s, 2H), 5.38 (br s, 2H), 2.70 (q, 4H, J=7.0 Hz), 1.09 (t, 6H, J=7.6 Hz). ¹³C NMR (150 MHz, dmso-d₆) δ 159.25, 144.46, 143.22, 132.35, 128.40, 127.14, 27.02, 16.15. ESI-HRMS Calc m/z for C₁₂H₁₉N₄ 219.1604 (M+H)⁺, found 219.1615. HPLC 96.24% purity t_(R)=7.95 min.

Example 130 1-(1-(2,6-dichlorophenyl)-1H-pyrazol-5-yl)guanidine (JM1-285-2)

KO^(t)Bu (74 mg, 0.66 mmol) was added to a solution of 1-(2,6-dichlorophenyl)-1H-pyrazol-5-amine (100 mg, 0.44 mmol) in THF (5 mL) and stirred for 30 min at rt. To this mixture was added methyl carbamimidothioate sulfate (122 mg, 0.44 mmol) and refluxed for overnight. The compound was extracted with ether and evaporated to yield final compound as brown solid (Yield; 42%). ¹H NMR (cd₃od, 600 MHz) δ 9.02 (s, 1H), 7.71 (d, 1H, J=8.2 Hz), 7.61 (t, 1H, J=8.2 Hz), 7.42 (s, 1H), 5.46 (s, 1H). ¹³C NMR (150 MHz, cd₃od) δ 156.75, 150.34., 140.95, 139.57, 135.75, 134.25, 128.90, 89.23. ESI-HRMS Calc m/z for C₁₀H₁₀Cl₂N₅ 270.0308 (M+H)⁺, found 270.0316. HPLC 96.05% purity t_(R)=4.86 min.

Example 131 (E)-2-(2,6-dichlorobenzylidene)-N-phenylhydrazine-1-carboximidamide hydroiodide (JM2-175-2)

To a solution of methyl-2-(2,6-dichlorobenzylidene)hydrazine-1-carbimidothioate hydroiodide (100 mg, 0.25 mmol) in EtOH (4 mL) was added aniline (47 mg, 0.50 mmol). The mixture was stirred at reflux for overnight. The EtOH was evaporated and the triturated with ether to yield crude product as precipitate. The precipitate was filtered and washed with ether to get the final compound as light yellow solid (64%). ¹H NMR (cd₃od, 600 MHz) δ 11.90 (s, 1H), 10.15 (br s, 1H), 8.50 (s, 1H), 8.10 (br s, 2H), 7.55 (d, 2H, J=7.8 Hz), 7.40 (t, 1H, J=7.8 Hz), 7.30-7.25 (m, 3H). ¹³C NMR (150 MHz, cd₃od) δ 153.0, 143.0, 134.2, 131.2, 128.9, 128.1, 127.8, 126.6, 124.0. ESI-HRMS Calc m/z for C₁₄H₁₃Cl₄N₄ 307.0512 (M+H)⁺, found 307.0506. HPLC 97.80% purity t_(R)=7.90 min.

Example 132 (E)-2-(2,6-dichlorobenzylidene)hydrazine-1-carboximidamide bicarbonate (JM2-185-2)

A solution of 1,3-dichloro-2-(chloromethyl)benzene (100 mg, 0.51 mmol) and aminoguanidine bicarbonate (69 mg, 0.51 mmol) was refluxed overnight in EtOH (5 mL). The solvent was evaporated and purified on silica with 0-10% methanol in dichloromethane to yield final compound as white solid (58%). ¹H NMR (cd₃od, 600 MHz) δ 7.53 (d, 2H, J=7.58 Hz), 7.32 (t, 1H, J=7.09 Hz), 5.04 (s, 2H). ¹³C NMR (150 MHz, dmso-d₆) δ 158.74, 136.89, 131.10, 128.89, 128.48, 48.90. ESI-HRMS Calc m/z for C₈H₁₁Cl₂N₄ 233.0355 (M+H)⁺, found 233.0350. HPLC 96.78% purity t_(R)=6.52 min.

Example 133 (E)-2-(4-(benzyloxy)-2,6-dichlorobenzylidene)hydrazine-1-carboximidamide acetate(JM2-195-2)

¹H NMR (dmso-d₆, 600 MHz) δ 8.09 (s, 1H), 7.41 (d, 2H, J=7.0 Hz), 7.37 (t, 2H, d, J=7.0 Hz), 7.31 (t, 1H, J=7.0 Hz), 7.15 (s, 2H), 5.71 (s, 2H), 5.61 (s, 2H), 5.15 (s, 2H), 1.86 (s, 3H). ¹³C NMR (150 MHz, dmso-d₆) δ 161.50, 157.59, 138.21, 136.65, 134.24, 128.89, 128.05, 128.51, 124.98, 116.02, 70.19, 22.18. ESI-HRMS Calc m/z for C₁₅H₁₅Cl₂N₄O 337.0617 (M+H)⁺, found 337.0612. HPLC 99.64% purity t_(R)=8.02 min.

Example 134 Biological Activity Evaluation Analgesic Potency Evaluation by Hot Plate and Tail Flick Assay

Mice 4-6 week old were purchased and allowed a one week acclimation period with free access to food and water. Animals are brought to the testing room 60 minutes prior to the beginning of testing for acclimation to the room.

A regulated hot plate was set at 55 degrees C. and monitored continuously. For treatment, animals were treated with test compound or vehicle using the determined route and dose. Treatment times were staggered to achieve standard testing times. Testing was begun 15 minutes post injection. A single animal was placed on the hotplate and the time lapse between the mouse being placed on the hot plate and the time it first shows a nociceptive response, by licking its back paws or jumping off, was recorded. The cutoff time for all animals was 30 seconds. Any animal that did not show a response before to the cut off time was returned to their cage and their time was recorded as 30 seconds.

For the tail flick test, mice were gently restrained in a cloth; the tail flick beam was centered on the dorsal surface of the tail (about 2-3 cm from the base). The heat source was activated, and the latency for withdrawal of the tail was recorded. The intensity of the tail flick beam was adjusted so that the average withdrawal time of the baseline measurement was 2 to 4 sec. For each animal, a baseline response latency was determined in two consecutive responses measured at 5 min intervals. Animals were tested at 15, 30, 45 and 60 min after drug administration (Table 1). To protect against tissue injury, the test was terminated after 10 sec if the animal did not withdraw its tail. Results for representative compounds are shown in the following Table 1.

In some experiments combination of two drugs (morphine+GA and/or its analogs or acetaminophen+GA and/or its analogs) were tested around their determined ED50 values. Experimental protocols listed in the following article were adapted.

Stone L S, German J P, Kitto K F, Fairbanks C A, Wilcox G L. Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects. PLoS One. 2014; 9(10):e109903. doi: 10.1371/journal.pone.0109903. Blood pressure and body temperature measurements were also conducted as listed in this article.

TABLE 1 Tail flick latencies induced by representative compounds. (dose 2 mg/kg by subcutaneous route unless stated otherwise) Mean SEM Mean SEM JM1-191-2 JM1-195-2 % MPE 15 min 5.5 4.5 % MPE 15 min 5.0 1.6 30 min 7.8 3.0 30 min 14.9 5.0 45 min 8.1 3.9 45 min 16.8 9.0 60 min 2.5 4.1 60 min 17.6 7.3 JM2-171-2 JM2-185-2 % MPE 15 min 34.8 9.1 % MPE 15 min 13.0 2.6 30 min 72.1 19.7 30 min 7.1 1.2 45 min 79.7 16.7 45 min −4.3 1.5 60 min 94.8 5.2 60 min 5.0 2.0 JM2-195-2 JM2-175-2 % MPE 15 min 15.9 6.4 % MPE 15 min 3.2 3.4 30 min 6.3 4.7 30 min 11.1 5.5 45 min 6.2 5.0 45 min 4.7 3.0 60 min 6.2 1.7 60 min 5.7 5.5 JM2-233-2 JM2-253-2 % MPE 15 min 6.9 2.3 % MPE 15 min 10.8 4.7 30 min 0.4 2.5 30 min 2.1 3.0 45 min 7.3 4.5 45 min 3.3 4.1 60 min 3.4 4.7 60 min −0.9 3.9 JM2-269-2 JM2-257-2 % MPE 15 min 6.3 1.5 % MPE 15 min 14.0 5.4 30 min 15.5 1.9 30 min 2.9 3.5 45 min 12.7 2.5 45 min 8.1 5.8 60 min 11.2 0.3 60 min 9.8 2.1 JM2-255-2 JM2-287-2 % MPE 15 min 9.4 2.7 % MPE 15 min 4.8 5.0 30 min 17.3 5.3 30 min 11.2 1.8 45 min 15.1 4.1 45 min 22.9 7.3 60 min 11.7 2.3 60 min 41.0 8.3 JM2-83-2 JM1-175-2 % MPE 15 min 15.1 6.3 % MPE 15 min 26.7 10.7 30 min 13.5 4.2 30 min 45.0 14.0 45 min 16.6 4.7 45 min 55.1 16.0 60 min 32.5 11.9 60 min 58.1 15.8 75 min 37.8 12.9 75 min 39.9 13.2 90 min 37.2 11.9 90 min 30.8 7.5 105 min  27.9 10.7 120 min  49.8 12.4 135 min  45.8 16.0 150 min  47.7 14.5 JM2-109-2 JM2-275-2 % MPE 15 min 23.5 11.7 % MPE 15 min 4.9 2.0 30 min 14.1 13.8 30 min 2.8 6.6 45 min 12.4 3.4 45 min 4.9 3.1 60 min 14.1 7.5 60 min 5.0 3.3 BC1-272-1 BC1-45-1 % MPE 15 min 76.7 23.1 % MPE 15 min 52.6 33.7 30 min 85.6 20.3 30 min 55.8 31.5 45 min 96.2 10.0 45 min 92.7 14.7 60 min 97.4 6.9 60 min 90.5 19.0 BC2-5-1 BC2-35-1 % MPE 15 min 16.8 20.2 % MPE 15 min 89.5 29.8 30 min 4.8 10.0 30 min 91.7 23.5 45 min 9.1 6.4 45 min 92.3 17.9 60 min 4.4 11.1 60 min 91.5 24.0 BC2-45-1 BC2-27-1 % MPE 15 min 57.6 48.9 % MPE 15 min 34.8 38.6 30 min 100.0 0.0 30 min 63.3 43.0 45 min 100.0 0.0 45 min 83.3 38.9 60 min 100.0 0.0 60 min 82.3 33.1 BC2-47-1 BC2-57-1 % MPE 15 min 80.1 28.5 % MPE 15 min 82.8 35.9 30 min 92.5 21.1 30 min 80.2 29.8 45 min 100.0 0.0 45 min 94.5 10.8 60 min 100.0 0.0 60 min 85.2 28.3 JM2-87-2 JM2-109-2 % MPE 15 min 24.2 3.0 % MPE 15 min 7.2 4.5 30 min 64.2 11.3 30 min 14.8 1.1 45 min 60.7 12.2 45 min 12.1 3.6 % MPE 15 min 7.9 2.1 % MPE 15 min 7.6 2.8 30 min 10.6 4.0 30 min 2.9 2.5 45 min 8.4 6.0 45 min 4.7 3.5 60 min 5.3 6.9 60 min 4.6 1.6 JM3-141-2 JM3-141-2 % MPE 15 min 6.0 5.2 % MPE 15 min 34.0 16.0 30 min 27.0 14.1 30 min 45.5 13.5 45 min 17.5 10.6 45 min 54.9 15.8 60 min 26.3 16.8 60 min 41.0 10.0 JM3-239-2 JM3-257-2 % MPE 15 min 16.6 4.8 % MPE 15 min 3.3 0.9 30 min 7.4 3.9 30 min 12.5 1.3 45 min 2.0 4.0 45 min 14.6 2.3 60 min 2.2 2.7 60 min 10.8 4.5 JM3-257-2 (10 mg/kg) Lofexidine HCl % MPE 15 min 18.9 7.1 % MPE 15 min 92.7 7.3 30 min 31.3 1.9 30 min 100.0 0.0 45 min 65.5 20.1 45 min 100.0 0.0 60 min 60.2 12.5 60 min 89.0 7.3 75 min 65.3 20.0 75 min 92.8 4.2 90 min 33.7 7.7 90 min 91.9 8.1 60 min 67.8 9.3 60 min 9.3 3.1 JM2-111-2 JM2-101-2 % MPE 15 min 6.8 3.8 % MPE 15 min 6.6 3.7 30 min 11.5 1.9 30 min 11.2 2.0 45 min 6.7 1.5 45 min 6.0 3.8 60 min 1.2 1.4 60 min 6.2 2.4 JM2-97-2 E-Guanabenz % MPE 15 min 87.1 12.9 % MPE 15 min 77.3 6.4 30 min 100.0 0.0 30 min 96.3 3.7 45 min 100.0 0.0 45 min 99.9 0.1 60 min 100.0 0.0 60 min 100.0 0.0 JM2-271-2 JM3-81-2 % MPE 15 min 5.4 1.6 % MPE 15 min 3.6 2.9 30 min 8.4 4.1 30 min 17.4 5.7 45 min 15.6 8.3 45 min 9.4 5.2 60 min 2.9 3.6 60 min 5.1 7.0 JM3-11-2 JM3-17-2 % MPE 15 min 7.0 2.4 % MPE 15 min 14.6 4.0 30 min 10.5 5.0 30 min 6.9 5.8 45 min 5.5 1.6 45 min −1.2 3.5 60 min 5.2 3.7 60 min 1.0 3.0 JM3-57-2 JM3-81-2 (10 mg/kg) % MPE 15 min 7.7 3.6 % MPE 15 min 55.9 18.0 30 min 5.6 3.2 30 min 59.3 18.9 45 min 9.0 5.3 45 min 68.0 19.1 60 min 3.2 4.7 60 min 76.2 16.7 JM3-89-2 JM3-131-2 % MPE 15 min 7.9 2.1 % MPE 15 min 7.6 2.8 30 min 10.6 4.0 30 min 2.9 2.5 45 min 8.4 6.0 45 min 4.7 3.5 60 min 5.3 6.9 60 min 4.6 1.6 JM3-141-2 JM3-141-2 % MPE 15 min 6.0 5.2 % MPE 15 min 34.0 16.0 30 min 27.0 14.1 30 min 45.5 13.5 45 min 17.5 10.6 45 min 54.9 15.8 60 min 26.3 16.8 60 min 41.0 10.0 JM3-239-2 JM3-257-2 % MPE 15 min 16.6 4.8 % MPE 15 min 3.3 0.9 30 min 7.4 3.9 30 min 12.5 1.3 45 min 2.0 4.0 45 min 14.6 2.3 60 min 2.2 2.7 60 min 10.8 4.5 JM3-257-2 (10 mg/kg) Lofexidine HCl % MPE 15 min 18.9 7.1 % MPE 15 min 92.7 7.3 30 min 31.3 1.9 30 min 100.0 0.0 45 min 65.5 20.1 45 min 100.0 0.0 60 min 60.2 12.5 60 min 89.0 7.3 75 min 65.3 20.0 75 min 92.8 4.2 90 min 33.7 7.7 90 min 91.9 8.1

Evaluation in the Cellular ER Stress Model

Hela Cells were seeded in 96 well plates at a density of 2,000 cells per well 24 hours prior to treatment. ER stress was elicited by addition of fresh media containing 1 μg/ml tunicamycin (Sigma-Aldrich). E-guanabenz (EGA) and the test compounds were dissolved in dimethyl sulfoxide (DMSO) and added as indicated. DMSO was used as a mock treatment. Cell viability was assessed by measuring the reduction of WST-8 [2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2, 4-disulfophenyl)-2H-tetrazolium] into formazan using Cell viability Counting Kit-8 (Dojindo) according to the supplier's recommendation, 48 hours after tunicamycin treatment. The optical density (OD) was read with a microplate reader (SpectraMax M5e, Molecular Devices). Concentration response graphs were generated for each drug using GraphPad Prism software (GraphPad Software, Ins., La Jolla, Calif.). Data for representative compounds is provided in the following Table.

TABLE Summary of Anti-ERS activity. % Cell Survival Compounds Cmpd(2.5 μM) + EGA(2.5 μM) + ERS EGA ERS Compounds Tuni Tuni Tuni (vs Tn) (vs Tn) JM2-83-2 53.75% 75.93% 43.02% 1.25 1.76 JM2-85-2 62.29% 75.93% 43.02% 1.45 1.76 JM2-97-2 63.14% 75.93% 43.02% 1.47 1.76 JM2-87-2 54.33% 67.87% 43.81% 1.24 1.55 JM2-89-2 56.88% 67.87% 43.81% 1.30 1.55 JM2-91-2 54.54% 67.87% 43.81% 1.24 1.55 JM2-95-2 52.99% 67.87% 43.81% 1.21 1.55 JM2-101-2 49.54% 68.84% 46.34% 1.07 1.49 JM2-103-2 48.66% 68.84% 46.34% 1.05 1.49 JM2-109-2 50.17% 68.84% 46.34% 1.08 1.49 BC1-267-2 42.28% 76.73% 41.63% 1.02 1.84 JM1-217-2 40.59% 76.73% 41.63% 0.97 1.84 JM1-285-2 41.94% 76.73% 41.63% 1.01 1.84 BC2-59-2 38.95% 76.73% 41.63% 0.94 1.84 BC2-7-1 66.66% 76.73% 41.63% 1.60 1.84 BC1-282-1 71.59% 76.73% 41.63% 1.72 1.84 JM1-113-2 27.64% 69.09% 36.76% 0.40 1.88 JM1-121-2 23.38% 69.09% 36.76% 0.34 1.88 JM1-129-2 24.07% 69.09% 36.76% 0.35 1.88 JM1-175-2 44.91% 69.09% 36.76% 0.65 1.88 JM1-185-2 54.37% 69.09% 36.76% 0.79 1.88 JM1-191-2 45.66% 69.09% 36.76% 0.66 1.88 JM1-221-2 38.58% 69.09% 36.76% 0.56 1.88 JM1-223-2 37.52% 69.09% 36.76% 0.54 1.88 JM1-225-2 35.89% 69.09% 36.76% 0.52 1.88 JM1-257-2 34.65% 69.09% 36.76% 0.50 1.88 JM2-59-2 46.19% 69.09% 36.76% 0.67 1.88 JM2-63-2 44.64% 69.09% 36.76% 0.65 1.88 JM2-111-1 34.62% 59.09% 31.64% 1.09 1.87 JM2-113-2 35.18% 59.09% 31.64% 1.11 1.87 JM2-115-2 35.58% 59.09% 31.64% 1.12 1.87 JM2-131-2 62.57% 59.09% 31.64% 1.98 1.87 JM2-133-2 57.15% 59.09% 31.64% 1.81 1.87 JM2-171-2 67.04% 59.09% 31.64% 2.12 1.87 JM2-175-2 34.31% 59.09% 31.64% 1.08 1.87 JM2-185-2 31.72% 59.09% 31.64% 1.00 1.87 JM2-191-2 39.48% 59.09% 31.64% 1.25 1.87 JM2-195-2 24.11% 59.09% 31.64% 0.76 1.87 JM2-253-2 39.58% 59.09% 31.64% 1.25 1.87 JM2-255-2 63.75% 59.09% 31.64% 2.01 1.87 JM2-275-2 29.84% 41.31% 29.61% 1.01 1.39 JM2-287-2 33.01% 41.31% 29.61% 1.11 1.39 JM2-233-2 31.75% 38.45% 26.34% 1.21 1.46 JM2-265-2 47.21% 38.45% 26.34% 1.79 1.46 JM2-271-2 32.32% 38.45% 26.34% 1.23 1.46 JM2-279-2 32.09% 38.45% 26.34% 1.22 1.46 JM2-289-2 33.75% 38.45% 26.34% 1.28 1.46 JM3-11-2 40.22% 38.45% 26.34% 1.53 1.46 JM3-13-2 27.41% 38.45% 26.34% 1.04 1.46 JM3-17-2 28.67% 38.45% 26.34% 1.09 1.46 JM3-27-2 28.65% 38.45% 26.34% 1.09 1.46 JM3-29-2 32.20% 38.45% 26.34% 1.22 1.46 JM3-57-2 28.07% 38.45% 26.34% 1.07 1.46 JM3-63-2 15.88% 38.45% 26.34% 0.60 1.46 Z-guanabenz 22.10% 40.02% 22.92% 0.96 1.75 JM3-67-2 23.33% 34.60% 22.94% 1.02 1.51 JM3-81-2 29.90% 34.60% 22.94% 1.30 1.51 JM3-89-2 22.02% 34.60% 22.94% 0.96 1.51 JM3-99-2 20.91% 34.60% 22.94% 0.91 1.51 JM3-131-2 22.83% 34.60% 22.94% 1.00 1.51 JM3-141-2 19.63% 34.60% 22.94% 0.86 1.51 JM3-149-2 29.08% 33.28% 23.22% 1.25 1.43 JM3-151-2 24.19% 33.28% 23.22% 1.04 1.43 JM3-153-2 35.95% 33.28% 23.22% 1.55 1.43 JM3-155-2 31.25% 33.28% 23.22% 1.35 1.43 JM3-161-2 14.65% 33.28% 23.22% 0.63 1.43 JM3-177-2 23.82% 33.28% 23.22% 1.03 1.43 JM3-179-2 20.40% 33.28% 23.22% 0.88 1.43 JM3-183-2 24.20% 33.28% 23.22% 1.04 1.43 JM3-191-2 40.62% 33.28% 23.22% 1.75 1.43 JM3-195-2 29.68% 33.28% 23.22% 1.28 1.43 JM3-181-2 19.60% 26.00% 19.17% 1.02 1.36 JM3-197-2 20.40% 26.00% 19.17% 1.06 1.36 JM3-199-2 22.92% 26.00% 19.17% 1.20 1.36 JM3-201-2 20.02% 26.00% 19.17% 1.04 1.36 JM2-203-2 19.74% 26.00% 19.17% 1.03 1.36 JM3-205-2 20.74% 26.00% 19.17% 1.08 1.36 JM3-207-2 23.08% 26.00% 19.17% 1.20 1.36 JM3-209-2 21.58% 26.00% 19.17% 1.13 1.36 JM3-211-2 20.22% 26.00% 19.17% 1.05 1.36 JM3-213-2 22.80% 26.00% 19.17% 1.19 1.36 JM3-215-3 21.01% 26.00% 19.17% 1.10 1.36 JM3-219-4 20.00% 26.00% 19.17% 1.04 1.36 JM3-221-2 28.94% 35.13% 23.66% 1.22 1.49 JM3-223-2 28.03% 35.13% 23.66% 1.18 1.49 JM3-225-2 22.76% 35.13% 23.66% 0.96 1.49 JM3-227-2 27.92% 35.13% 23.66% 1.18 1.49 JM3-239-2 28.08% 35.13% 23.66% 1.19 1.49 JM3-255-2 24.52% 35.13% 23.66% 1.04 1.49 JM3-257-2 31.25% 35.13% 23.66% 1.32 1.49 Salubrinal(25 μM) 38.46% 49.76% 33.22% 1.16 1.50 Lofexidine Hcl 35.43% 49.76% 33.22% 1.07 1.50 Sal003 33.17% 40.42% 32.23% 1.03 1.25 Calculations: ERS activity vs Tuni = % cell survival (compound)/% cell survival (tunicamycin)

The Enzyme-Linked Immunospot (Elispot) Cell Infection Assay for Anti-Prion Activity

The Elispot cell infection assay was adapted from previous studies (Mahal, S. P. et al. Proc Natl Acad Sci USA 104, 20908-20913; and Li, J. et al. Science 327, 869-872) with minor modifications (Table 2). Briefly, 200 μL of PMCA products at round 6 were collected and centrifuged at 100,000×g, 4° C. for 1 hour and the pellets were washed twice, followed by centrifugation at 100,000×g, 4° C. for 1 hour after each wash. After the final wash, the pellets were resuspended in 200 μL of CAD5 growth media (OPTI-MEM, 5% BGS and 1% penicillin and streptomycin) and sonicated for 30 seconds with 50% output (Misonic Sonicator XL2020). Each sample was serially diluted 10, 100, and 1,000 times and 60 μL of undiluted and diluted samples were used to infect CAD5 cells. After two 1:10 splits, 20,000 CAD5 cells/well were transferred to the Millipore 96-well Elispot plates (MSIPN4W) and subjected to the Elispot assay (Mahal, S. P. et al. Proc Natl Acad Sci USA 104, 20908-20913; and Li, J. et al. Science 327, 869-872). The images were taken by S6 Micro Analyzer (CTL Analyzers, LLC) and processed by the ImmunoSpot software (CTL Analyzers, LLC). The graph was generated using GraphPad Prism (GraphPad Software, Inc.) (FIGS. 1A and 1B).

TABLE 2 Anti-ERStress activity and anti-prion activity of representative compounds. EliSpot AntiERStress AntiPrion (Spots/10000 (% Cell (Number of ERS Elispot Compound Cells) Survival) Cells × 10⁴) (vs Tn) (vs PC) 1/Elispot BC1-167-1 1500 45.93192 9 0.95 1.15 0.87 BC1-171-1 1300 52.53729 16 1.08 1.00 1.00 BC1-242-2 700 57.56368 50 1.19 0.54 1.86 BC1-252-2 1800 49.48715 8 1.02 1.38 0.72 BC1-256-2 900 54.76512 32 1.13 0.69 1.44 BC1-259-2 800 62.86899 26 1.30 0.62 1.63 BC1-262-1 700 64.70308 53 1.34 0.54 1.86 BC1-267-2 1300 64.26003 18 1.33 1.00 1.00 BC1-272-2 1300 95.09492 15 1.96 1.00 1.00 BC1-282-1 1700 101.2576 10 2.09 1.31 0.76 Z-Guanabenz 2200 64.32858 3 1.33 1.69 0.59 BC1-295-1 600 60.58403 37 1.25 0.46 2.17 BC1-297-1 1400 90.49042 8 1.87 1.08 0.93 BC2-3-1 700 82.07256 28 1.69 0.54 1.86 BC2-5-1 800 104.9813 34 2.17 0.62 1.63 BC2-7-1 1300 100.0136 3 2.06 1.00 1.00 BC2-9-1 900 93.31728 33 1.93 0.69 1.44 BC2-11-1 800 52.43021 38 1.08 0.62 1.63 BC2-13-1 1800 68.97337 9 1.42 1.38 0.72 BC2-17-1 1300 104.8795 16 2.16 1.00 1.00 Sephin-1 800 87.19458 32 1.80 0.62 1.63 BC2-19-1 1800 64.14785 5 1.32 1.38 0.72 BC2-25-1 1200 51.70278 20 1.07 0.92 1.08 BC2-45-1 2100 99.19487 10 2.05 1.62 0.62 E-Guanabenz 800 94.70235 56 1.95 0.62 1.63 BC2-55-2 1300 70.68508 4 1.46 1.00 1.00 BC2-61-1 1400 86.55959 10 1.79 1.08 0.93 BC2-61-2 800 58.21462 50 1.20 0.62 1.63 BC2-59-1 1400 104.6895 15 2.16 1.08 0.93 Compound 7 1100 94.95489 15 1.96 0.85 1.18 Positive 1300 — 55 1.00 1.00 Control Input — — 2 Vehicle — 100 — tunicamycin — 48.46011 — Calculations: ERS activity vs Tn = % cell survival (compound)/% cell survival (tunicamycin) Elispot (vs positive control) = Elispot (spots/10000 cells) for (Compound)/Elispot (spots/10000 cells) for (Positive control) 1/Elispot = 1/[Elispot (vs positive control)] Higher (ERS activity vs Tn) or (1/Elispot) indicates better neuroprotective activity.

Protection Against Inflammation during Experimental Autoimmune Encephalomyelitis (EAE)

The MOG-induced EAE consists of the acute phase (the demyelination phase) and the chronic phase (the remyelination phase) (Lin W, et al. J Neurosci. 2013, 33:5980-5991; and Lin Y, et al. Am J Pathol. 2014, 184:507-519). Effect of treatment with the test compound was evaluated during the acute phase of EAE in terms of attenuation of mature oligodendrocyte apoptosis and demyelination. Eight-week-old female C57BL/6J mice were immunized with MOG35-55 peptide to induce EAE. Briefly, the mice received subcutaneous injections of 200 μg MOG35-55 peptide emulsified in complete Freund's adjuvant supplemented with 600 μg of mycobacterium tuberculosis in the flank and tail base. Two intraperitoneal injections of 400 ng of pertussis toxin were given 24 h and 72 h later. Mice were treated with the test compound or vehicle daily starting on post immunization day (PID) 10. Clinical severity scores was recorded daily using a 0-5 point scale (0=healthy, 1=flaccid tail, 2=ataxia and/or paresis of hind limbs, 3=paralysis of hind limbs, 4=tetra paralysis, and 5=moribund or dead) up to PID 35. Preliminary results showed that treatment with Sephin 1 markedly attended the EAE disease severity (FIG. 2).

Example 135 Biological Evaluation of Acetominiphen Toxicity

Compound BC1-45-1 (guanabenz) and representative compounds of formulae Ia′, Ib′, Ic′ and Id′ are capable of reducing serum ALT levels and liver necrosis in mice overdosed with acetaminophen. The hepatoprotection provided by compound BC1-45-1 is superior to the currently used clinical antidote N-acetyl cysteine. Accordingly, a combination of acetaminophen with compound BC1-45-1 or a compound of formulae Ia′, Ib′, Ic′ and Id′ could improve the therapeutic window, thus reducing the risk of liver toxicity.

The effects of compounds BC1-45-1 and BC1-55-1, as well as representative compounds of formulae Ia′, Ib′, Ic′ and Id′, on the hepatotoxicity of acetaminophen were evaluated in the following assay(s).

Representative compounds were tested using protocols similar to those described by More S S, Nugent J, Vartak A P, Nye S M, and Vince R. Chem Res Toxicol. 2017; 30(3):777-784. doi: 10.1021/acs.chemrestox.6b00291.

Results

FIG. 5A demonstrates that pretreatment with compound BC1-55-1 limited the hepatotoxicity of acetaminophen (APAP). The survival rate was 100% for the pretreated animals. FIG. 5B demonstrates that pretreatment with N-acetyl cysteine was less effective in limiting the hepatotoxicity of acetaminophen. Twenty-five percent of the animals treated with N-acetyl cysteine died before completion of the study.

FIG. 6A demonstrates that delayed administration of compound BC1-55-1 (0.5, 1, 2, 4 and 8 h post APAP administration) reduces elevated ALT levels after acetaminophen overdose. The survival rate was 100% for the animals treated with compound BC1-55-1. FIG. 6B demonstrates that delayed treatment with N-acetyl cysteine (1, 2 and 4 h) was less effective in limiting elevated ALT levels after acetaminophen overdose. Eighty-eight percent of the animals treated with N-acetyl cysteine four hours after acetaminophen overdose died before completion of the study.

The TBARS data in FIG. 7 demonstrates that pretreatment with compound BC1-55-1 limited the elevated lipid peroxidation byproducts as measured by the TBARS assay after acetaminophen overdose (2.8 fold increase over the vehicle control group).

FIGS. 8A and 8B demonstrate that representative compounds of formulae Ia′, Ib′, Ic′ and Id′ function as antidotes for acetaminophen induced hepatotoxicity.

FIG. 9A and B demonstrate that pretreatment and delayed treatment (0.5, 1, 2, 4, 6 and 8 h post acetaminophen administration) with compound BC1-45-1 (guanabenz) limited the hepatotoxicity of acetaminophen. The survival rate in all the BC1-45-1 treatments group was 100%.

FIG. 10A demonstrates analgesic synergy between acetaminophen and BC1-45-1 (guanabenz). Combination of these two compounds in various ratios ranging from 500:1 to 1000:1 for (acetaminophen: BC1-45-1) provided synergy at all the time points tested in the tail flick assay. Body temperature measurement (FIG. 10C) for this combination did not exhibit synergy in the hypothermic action of acetaminophen. BC1-45-1 did not have any effect on the hypothermic action of acetaminophen.

Example 136 Biological Evaluation of Antiviral Activity Against HSV

The antiviral activity of the following representative compounds was evaluated in a plaque reduction assay.

Number SW Number BC1-45-1 (E-GA) SW1 BC1-55-1 (Z-GA) SW2 BC1-272-1 SW3 BC1-282-1 SW4 BC1-283-1 SW5 BC1-297-1 SW6 BC2-5-1 SW7 BC2-7-1 SW8 BC2-9-1 SW9 BC2-13-1 SW10 BC2-17-1 SW11 BC2-45-1 SW12 BC2-59-2 SW13 JM1-185-2 SW14 JM2-85-2 SW15 JM2-97-2 SW16 JM2-131-2 SW17 JM2-133-2 SW18 JM2-171-2 SW19 JM2-233-2 SW20 JM2-255-2 SW21 JM2-265-2 SW22 JM2-271-2 SW23 JM2-279-2 SW24 JM2-289-2 SW25 JM3-11-2 SW26 JM3-29-2 SW27 JM2-53-2 (Sal 003) SW28 JM3-177-2 (Sal) SW29 JM3-191-2 SW30 JM3-195-2 SW31 BC1-299-1 SW32

-   Approach: Test compounds for their ability to prevent HSV infection     and spread in cell culture. -   Method: Plaque Reduction Assay. (1) Plate Vero cells into 24-well     dish (1×10⁵ per well). (2) Next day, add test compounds or control     inhibitor, ganciclovir (GCV), to cells. (3) The next day, remove     medium and add 300 μL of HSV-1 KOS strain (200 plaque forming units     per well) to 2 wells per compound. After two hours, test compound     was added in 2% methylcellulose-containing medium. This medium is to     promote plaque formation. (4) Three days later, medium is removed     and cells are fixed/stained with MeOH and giemsa. Plaques are     counted microscopically. -   Reagents: (1) SM compounds screened at 2.5 μM final     concentration. (2) GCV used at 1 μM final concentration. (3)     HSV-1(KOS) is a lab strain and the stock virus concentration is     about 6.7×10⁹ plaque forming units per mL. -   Data: Antiviral data for the compounds identified above is provided     in FIGS. 11A, 11B, and 11C.

Example 137

The following illustrate representative pharmaceutical dosage forms, containing a compound of formula Ia′, Ib′, Ic′ or Id′ (compound X), for therapeutic or prophylactic use in humans.

(i) Tablet 1 ms/tablet Compound X = 100.0 Lactose 77.5 Povidone 15.0 Croscarmellose sodium 12.0 Microcrystalline cellulose 92.5 Magnesium stearate 3.0 300.0

(ii) Tablet 2 mg/tablet Compound X = 20.0 Microcrystalline cellulose 410.0 Starch 50.0 Sodium starch glycolate 15.0 Magnesium stearate 5.0 500.0

(iii) Capsule mg/capsule Compound X = 10.0 Colloidal silicon dioxide 1.5 Lactose 465.5 Pregelatinized starch 120.0 Magnesium stearate 3.0 600.0

(iv) Injection 1 (1 mg/ml) mg/ml Compound X = (free acid form) 1.0 Dibasic sodium phosphate 12.0 Monobasic sodium phosphate 0.7 Sodium chloride 4.5 1.0N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

(v) Injection 2 (10 mg/ml) mg/ml Compound X = (free acid form) 10.0 Monobasic sodium phosphate 0.3 Dibasic sodium phosphate 1.1 Polyethylene glycol 400 200.0 1.0N Sodium hydroxide solution q.s. (pH adjustment to 7.0-7.5) Water for injection q.s. ad 1 mL

(vi) Aerosol mg/can Compound X = 20.0 Oleic acid 10.0 Trichloromonofluoromethane 5,000.0 Dichlorodifluoromethane 10,000.0 Dichlorotetrafluoroethane 5,000.0 The above formulations may be obtained by conventional procedures well known in the pharmaceutical art.

All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention. 

What is claimed is:
 1. A compound of formula Ia′, Ib′ Ic′, or Id′:

or a pharmaceutically acceptable salt thereof; i) wherein the compound of formula Ia′: ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN; L is selected from the group consisting of: —CH₂CH₂—, —CH₂NH—, —CH₂C(═O)—, —CH(OH)CH₂—,

R^(L) is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl or C₃₋₈ cycloalkyl; ring Y is heteroaryl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(y), —SR^(y), —N(R^(y))₂, —NO₂ or —CN; R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(f))₂, oxo, —NO₂ or —CN; or R⁶ and R⁸ taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN; R⁸ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN; or R⁶ and R⁸ taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; X is ═O, ═S or ═N—Rx; wherein R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))2, —NO₂ or —CN; each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(g)is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and each R^(y) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(y) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; ii) wherein the compound of formula Ib′: ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN; Y is S or —NR⁶—; R⁶ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(f), —SR^(f), —N(R^(a))₂, oxo, —NO₂ or —CN; R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN; R⁸ is hydrogen, phenyl, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(h), —SR^(h), —N(R^(h))₂, oxo, —NO₂ or —CN; R^(x) is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; or R^(x) and R⁸ taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(b) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(b) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(c) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(c) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(d) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(d) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(f) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(f) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(h) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(h) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; iii) wherein the compound of formula Ic′: ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN; L is —CH═N—, or C₁₋₄ alkylene that is optionally substituted with one or more groups selected from halo, hydroxy or C₃₋₈ cycloalkyl; R⁷ is hydrogen, or C₁₋₆ alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR^(g), —SR^(g), —N(R^(g))₂, oxo, —NO₂ or —CN; ring Z is heteroaryl or unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from oxo (═O), C₁₋₄ alkyl, —F, —Cl, —Br, —I, —OR^(i), —SR^(i), —N(R^(i))₂, —NO₂ or —CN; each R^(a) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(a) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(e) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl, wherein the C₁₋₄ alkyl and C₁₋₄ haloalkyl are optionally substituted with aryl or heteroaryl; or two R^(e) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; each R^(g) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(g) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and each R^(i) is independently hydrogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; or two R^(i) groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; iv) wherein the compound of formula Id′: ring A is phenyl, napthyl, thienyl, or 6-membered heteroaryl, which phenyl, napthyl, thienyl, or 6-membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ and —CN; and R⁹ is hydrogen or C(═NH)—NH₂. provided that the compound is not:


2. The compound of claim 1 that is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 3. A pharmaceutical composition comprising a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in claim 1, and a pharmaceutically acceptable carrier.
 4. A method for producing analgesia in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′ or a pharmaceutically acceptable salt thereof as described in claim
 1. 5. The method of claim 4 further comprising administering morphine to the animal.
 6. The method of claim 4, wherein the compound is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein: ring A is phenyl; R¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN; R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN; R³ is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —SR^(c), —N(R^(c))₂, —NO₂ or —CN; R⁴ is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN; R⁵ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN; and the group


7. The method of claim 4, wherein the compound is a compound of the following formula:

wherein: R¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(a), —SR^(a), —N(R^(a))₂, —NO₂ or —CN; R² is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(b), —SR^(b), —N(R^(b))₂, —NO₂ or —CN; R³ is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(c), —N(R^(c))₂, —NO₂ or —CN; R⁴ is hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(d), —SR^(d), —N(R^(d))₂, —NO₂ or —CN; R⁵ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₃₋₈ cycloalkyl, —F, —Cl, —Br, —I, —OR^(e), —SR^(e), —N(R^(e))₂, —NO₂ or —CN; and L is selected from the group consisting of —NH—, —CH₂NH—, —CH₂C(═O)—,

and C₁₋₄ alkylene that is optionally substituted with one or more groups selected from halo, hydroxy and C₃₋₈ cycloalkyl.
 8. The method of claim 4, wherein the compound is


9. The method of claim 5, wherein the analgesia is produced for synergy in antinociception with reduced sedation or cardiovascular effects.
 10. The composition of claim 3 further comprising acetaminophen.
 11. The composition of claim 10 wherein the compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof is E-guanabenz or Z-guanabenz, or a pharmaceutically acceptable salt thereof.
 12. The method of claim 4 further comprising administering acetaminophen to the animal.
 13. The method of claim 12 wherein the compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof is E-guanabenz or Z-guanabenz, or a pharmaceutically acceptable salt thereof.
 14. A pharmaceutical composition comprising: 1) a drug that is associated with unwanted endoplasmic reticulum stress, 2) a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in claims 1, and 3) a pharmaceutically acceptable carrier; provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not

or a pharmaceutically acceptable salt thereof.
 13. A method for reducing endoplasmic reticulum stress in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in claim 1; provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not

or a pharmaceutically acceptable salt thereof.
 14. A method for reducing drug-induced toxicity in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in claim
 1. 15. The method of claim 14 wherein the drug is acetaminophen.
 16. A method for treating a disease selected from the group consisting of diabetes, viral infection, and cancer in an animal comprising administering to the animal a compound of formula Ia′, Ib′ Ic′, or Id′, or a pharmaceutically acceptable salt thereof as described in claim 1; provided the compound of formula Ia′, Ib′ Ic′, or Id′ is not

or a pharmaceutically acceptable salt thereof. 